Pyrimidine-2-amine compounds and their use as inhibitors of JAK kinases

ABSTRACT

This invention is directed to methods of treating diseases or conditions associated with JAK2 activity in a mammal comprising the administration of a compound of formula (I): 
                         
where
 
                         
n, m, Y, R 1 , R 2 , R 3 , R 4  and R 5  are disclosed herein, or a pharmaceutically acceptable salt.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.13/619,843, filed Sep. 14, 2012, now allowed; which is a divisional ofU.S. patent application Ser. No. 12/371,550, filed Feb. 13, 2009, nowU.S. Pat. No. 8,309,566; which claims the benefit under 37 U.S.C.§119(e) of U.S. Provisional Patent Application No. 61/029,265, filedFeb. 15, 2008; U.S. Provisional Patent Application No. 61/038,672, filedMar. 21, 2008; and U.S. Provisional Patent Application No. 61/112,046,filed Nov. 6, 2008. These applications are incorporated herein byreference in their entireties.

FIELD OF THE INVENTION

The present invention relates to compounds, or pharmaceuticallyacceptable salts thereof, and pharmaceutical compositions comprising thecompounds or salts which are useful as modulators of the JAK pathway oras inhibitors of JAK kinases, particularly JAK2. This invention is alsodirected to methods of using the compounds or pharmaceuticallyacceptable salts and pharmaceutical compositions thereof in treatingdiseases and conditions associated with JAK activity.

BACKGROUND OF THE INVENTION

Protein kinases constitute a large family of structurally relatedenzymes that are responsible for the control of a variety of signaltransduction processes within cells (see, e.g., Hardie and Hanks, TheProtein Kinase Facts Book, I and II, Academic Press, San Diego, Calif.,1995). Protein kinases are thought to have evolved from a commonancestral gene due to the conservation of their structure and catalyticfunction. Almost all kinases contain a similar 250-300 amino acidcatalytic domain. The kinases can be categorized into families by thesubstrates they phosphorylate (e.g., protein-tyrosine,protein-serine/threonine, lipids, etc.). Sequence motifs have beenidentified that generally correspond to each of these families (see,e.g., Hanks & Hunter, (1995), FASEB J. 9:576-596; Knighton et al.,(1991), Science 253:407-414; Hiles et al., (1992), Cell 70:419-429; Kunzet al., (1993), Cell 73:585-596; Garcia-Bustos et al., (1994), EMBO J.13:2352-2361).

JAK kinases (JAnus Kinases) are a family of cytoplasmic protein tyrosinekinases including JAK1, JAK2, JAK3 and TYK2. Each of the JAK kinases isselective for the receptors of certain cytokines, though multiple JAKkinases can be affected by particular cytokine or signaling pathways.Studies suggest that JAK3 associates with the common gamma (γc) chain ofthe various cytokine receptors. JAK3, in particular, selectively bindsto receptors and is part of the cytokine signaling pathway for IL-2,IL-4, IL-7, IL-9, IL-15 and IL-21. JAK1 interacts with, among others,the receptors for cytokines IL-2, IL-4, IL-7, IL-9 and IL-21, while JAK2interacts with, among others, the receptors for IL-9 and TNF-α. Upon thebinding of certain cytokines to their receptors (e.g., IL-2, IL-4, IL-7,IL-9, IL-15 and IL-21), receptor oligomerization occurs, resulting inthe cytoplasmic tails of associated JAK kinases being brought intoproximity and facilitating the trans-phosphorylation of tyrosineresidues on the JAK kinase. This trans-phosphorylation results in theactivation of the JAK kinase.

Phosphorylated JAK kinases bind various STAT (Signal Transducer andActivator of Transcription) proteins. STAT proteins, which are DNAbinding proteins activated by phosphorylation of tyrosine residues,function both as signaling molecules and transcription factors andultimately bind to specific DNA sequences present in the promoters ofcytokine-responsive genes (Leonard et al., (2000), J. Allergy Clin.Immunol. 105:877-888). JAK/STAT signaling has been implicated in themediation of many abnormal immune responses such as allergies, asthma,autoimmune diseases such as transplant (allograft) rejection, rheumatoidarthritis, amyotrophic lateral sclerosis and multiple sclerosis, as wellas in solid and hematologic malignancies such as leukemia and lymphomas.For a review of the pharmaceutical intervention of the JAK/STAT pathwaysee Frank, (1999), Mol. Med. 5:432:456 and Seidel et al., (2000),Oncogene 19:2645-2656.

As described above, JAK's are crucial components of diverse signaltransduction pathways that govern important cellular functions,including cell survival, proliferation, differentiation and apoptosis.Interfering with JAK activity may lead to the loss of a vital signaltransduction pathway, thereby disrupting normal cellular processesneeded for cell survival. Therefore, it is important to selectivelyinhibit particular JAK's that are involved in various disease states.

JAK2 associates with cytokine receptors and is essential for signaltransduction by mediating tyrosine phosphorylation. JAK2 activity isregulated by a series of interactions, beginning with binding tospecific domains in receptors, suppression of activation by thepseudokinase domain, and the requirement for phosphorylation within theactivation loop. Recent studies have implicated deregulation of JAK2kinase activity by chromosomal translocations in hematopoietic tumorsand mutations within the pseudokinase domain in a spectrum ofmyeloproliferative diseases (Ihle, J N et al., Current Opinion inGenetics and Development (2007) 17:1, 8-14.

In addition, JAK2 has been suggested to be involved in the upregulationof angiotensinogen promoter activity in hypertrophy and ischemia(Mascareno E, et al. (2000) Mol. Cell. Biochem., 212:171-175; andMascareno E, et al. (2001) Circulation, 104:1). One particulartyrphostin, AG490, selectively inhibits JAK2 and has been proposed fortreating cancer (Meydan N, et al. (1996) Nature, 379:645).Administration of tyrphostin AG490 has been suggested to affordcardioprotection to hearts subjected to ischemia/reperfusion (MascarenoE, et al. (2000) Mol. Cell. Biochem., 212:171 and Mascareno E, et al.(2001) Circulation, 104:1). TG101209, a JAK2-selective compound, hasbeen recently shown to be effective in inhibiting mutations inmyeloproliferative disorders (Pardanani A, et al. (2007) Leukemia,1-11).

JAK3, in particular, has been implicated in a variety of biologicalprocesses. For example, the proliferation and survival of murine mastcells induced by IL-4 and IL-9 have been shown to be dependent on JAK3-and gamma chain-signaling (Suzuki et al., (2000), Blood 96:2172-2180).JAK3 also plays a crucial role in IgE receptor-mediated mast celldegranulation responses (Malaviya et al., (1999), Biochem. Biophys. Res.Commun. 257:807-813), and inhibition of JAK3 kinase has been shown toprevent type I hypersensitivity reactions, including anaphylaxis(Malaviya et al., (1999), J. Biol. Chem. 274:27028-27038). JAK3inhibition has also been shown to result in immune suppression forallograft rejection (Kirken, (2001), Transpl. Proc. 33:3268-3270). JAK3kinases have also been implicated in the mechanism involved in early andlate stages of rheumatoid arthritis (Muller-Ladner et al., (2000), J.Immunol. 164:3894-3901); familial amyotrophic lateral sclerosis (Trieuet al., (2000), Biochem Biophys. Res. Commun. 267:22-25); leukemia(Sudbeck et al., (1999), Clin. Cancer Res. 5:1569-1582); mycosisfungoides, a form of T-cell lymphoma (Nielsen et al., (1997), Prac.Natl. Acad. Sci. USA 94:6764-6769); and abnormal cell growth (Yu et al.,(1997), J. Immunol. 159:5206-5210; Catlett-Falcone et al., (1999),Immunity 10:105-115).

The JAK kinases, including JAK3, are abundantly expressed in primaryleukemic cells from children with acute lymphoblastic leukemia, the mostcommon form of childhood cancer, and studies have correlated STATactivation in certain cells with signals regulating apoptosis (Demoulinet al., (1996), Mol. Cell. Biol. 16:4710-6; Jurlander et al., (1997),Blood. 89:4146-52; Kaneko et al., (1997), Clin. Exp. Immun. 109:185-193;and Nakamura et al., (1996), J. Biol. Chem. 271:19483-8). They are alsoknown to be important to lymphocyte differentiation, function andsurvival. JAK-3, in particular, plays an essential role in the functionof lymphocytes, macrophages, and mast cells. Given the importance ofthis JAK kinase, compounds which modulate the JAK pathway, includingthose selective for JAK3, can be useful for treating diseases orconditions where the function of lymphocytes, macrophages, or mast cellsis involved (Kudlacz et al., (2004) Am. J. Transplant 4:51-57;Changelian (2003) Science 302:875-878). Conditions in which targeting ofthe JAK pathway or modulation of the JAK kinases, particularly JAK3, arecontemplated to be therapeutically useful include leukemia, lymphoma,transplant rejection (e.g., pancreas islet transplant rejection), bonemarrow transplant applications (e.g., graft-versus-host disease),autoimmune diseases (e.g., RA, type I diabetes), and inflammation (e.g.,asthma, allergic reactions). Conditions which can benefit for inhibitionof JAK2 are discussed in greater detail below.

In view of the numerous conditions that are contemplated to benefit bytreatment involving modulation of the JAK pathway, it is immediatelyapparent that new compounds that modulate JAK pathways and methods ofusing these compounds should provide substantial therapeutic benefits toa wide variety of patients.

RELATED DISCLOSURES

Patents and patent applications related to modulation of the JAK pathwayinclude: U.S. Pat. Nos. 5,728,536; 6,080,747; 6,080,748; 6,133,305;6,177,433; 6,210,654; 6,313,130; 6,316,635; 6,433,018; 6,486,185;6,506,763; 6,528,509; 6,593,357; 6,608,048; 6,610,688; 6,635,651;6,677,368; 6,683,082; 6,696,448; 6,699,865; 6,777,417; 6,784,195;6,825,190; 6,506,763; 6,784,195; 6,528,509; 6,608,048; 7,105,529;6,699,865; 6,825,190; 6,815,439; 6,949,580; 7,056,944; 6,998,391;7,074,793; 6,969,760; U.S. Pat. App. Pub. Nos. 2001/0007033 A1;2002/0115173 A1; 2002/0137141 A1; 2003/0236244 A1; 2004/0102455 A1;2004/0142404 A1; 2004/0147507 A1; and 2004/0214817 A1; and InternationalPublished Patent Application Nos. WO 95/03701A1; WO 99/15500A1; WO00/00202A1; WO 00/10981A1; WO 00/47583A1; WO 00/51587A2; WO 00/55159A2;WO 01/42246A2; WO 01/45641A2; WO 01/52892A2; WO 01/56993A2; WO01/57022A2; WO 01/72758A1; WO 02/00661A1; WO 02/43735A1; WO 02/48336A2;WO 02/060492A1; WO 02/060927A1; WO 02/096909A1; WO 02/102800A1; WO03/020698A2; WO 03/048162A1; WO 03/101989A1; WO 2004/016597A2; WO2004/041789A1; WO 2004/041810A1; WO 2004/041814A1; WO 2004/046112A2; WO2004/046120A2; WO 2004/047843A1; WO 2004/058749A1; WO 2004/058753A1; WO2004/085388A2; WO 2004/092154A1; WO 2005/009957A1; WO 2005/016344A1; WO2005/028475A2; and WO 2005/033107A1.

All of the above publications are herein incorporated by reference intheir entireties to the same extent as if each individual publicationwas specifically and individually indicated to be incorporated byreference in its entirety.

SUMMARY OF THE INVENTION

This invention is directed to 2-pyrimidineamine compounds, orpharmaceutically acceptable salts thereof, and pharmaceuticalcompositions comprising the compounds or pharmaceutically acceptablesalts thereof, for use in the treatment of conditions in whichmodulation of the JAK pathway or inhibition of JAK kinases, particularlyJAK2, can be therapeutically useful.

Accordingly, in one aspect, this invention is directed to compounds offormula (I):

and pharmaceutically acceptable salts thereof, wherein:

is selected from the group consisting of a six-membered aryl and asix-membered heteroaryl;

-   n is 0, 1 or 2;-   m is 0, 1, 2, 3 or 4;-   R¹ is selected from the group consisting of hydrogen, alkyl,    alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkenyl, optionally    substituted cycloalkyl, optionally substituted cycloalkylalkyl,    optionally substituted cycloalkylalkenyl, optionally substituted    cycloalkylalkynyl, optionally substituted aryl, optionally    substituted aralkyl, optionally substituted aralkenyl, optionally    substituted aralkynyl, —R⁸—C(O)OR⁶, —R⁹—N(R⁶)R⁷ and —R⁹—OR⁶;-   each R², when present, is independently selected from the group    consisting of optionally substituted alkyl, halo, haloalkyl, cyano,    nitro, —OR⁶, —N(R⁶)₂, —C(O)OR⁶ and —C(O)N(R⁶)₂;-   each R³, when present, is independently selected from the group    consisting of alkyl, halo and haloalkyl;-   R⁴ is selected from the group consisting of aryl and heteroaryl,    where the aryl and the heteroaryl are each independently optionally    substituted by one or more substituents selected from the group    consisting of oxo, alkyl, halo, haloalkyl, cyano, N-heterocyclyl,    N-heteroaryl, aryl, —R⁸—OR^(6a), —R⁸—S(O)_(p)R^(6a) (where p is 0, 1    or 2), —R⁸—C(O)R^(6a), —R⁸—C(O)OR^(6a), —R⁸—C(O)N(R^(6a))R^(7a),    —R⁸—N(R^(6a))R^(7a), —R⁸—N(R^(6a))—R⁹—N(R^(6a))R^(7a),    —R⁸—N(R^(6a))—R⁹—OR^(7a), —R⁸—N(R^(6a))C(O)R^(7a),    —R⁸—N(R^(6a))S(O)₂R^(7a), —R⁸—N(R^(6a))C(O)—R⁸—N(R^(6a))R^(7a), and    —R⁸—N(R^(6a))—R⁹—N(R^(6a))S(O)₂R^(7a), where each R^(6a) and R^(7a)    is independently selected from the group consisting of hydrogen,    alkyl, optionally substituted cycloalkyl, optionally substituted    heterocyclyl, optionally substituted heterocyclylalkyl, optionally    substituted heteroaryl and optionally substituted aralkyl, and where    the N-heterocyclyl, the N-heteroaryl and the aryl are each    independently optionally substituted by one or more substituents    selected from the group consisting of —C(O)R⁶, —R⁸—N(R⁶)R⁷,    —R⁸—C(O)N(R⁶)R⁷, alkyl, halo and optionally substituted aryl;-   R⁵ is an N-heterocyclyl, wherein a nitrogen atom in the    N-heterocyclyl is optionally substituted by a substituent selected    from the group consisting of alkyl, alkenyl, alkynyl, haloalkyl,    haloalkenyl, haloalkynyl, optionally substituted aryl, optionally    substituted aralkyl, optionally substituted aralkenyl, optionally    substituted aralkynyl, optionally substituted cycloalkyl, optionally    substituted cycloalkylalkyl, optionally substituted    cycloalkylalkenyl, optionally substituted cycloalkylalkynyl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, optionally substituted heterocyclylalkenyl,    optionally substituted heterocyclylalkynyl, optionally substituted    heteroaryl, optionally substituted heteroarylalkyl, optionally    substituted heteroarylalkenyl, optionally substituted    heteroarylalkynyl, —R⁸—OR⁶, —R⁸—C(O)R⁶, —R⁸—C(O)OR⁶, —R⁹—N(R⁶)R⁷,    —R⁸—C(O)N(R⁶)R⁷, —R⁸—C(N═R⁶)N(R⁶)R⁷, —R⁸—S(O)₂N(R⁶)R⁷, and    —R⁸—S(O)_(t)R⁶ (where t is 1 or 2); and a carbon atom in the    N-heterocyclyl is optionally substituted by a substituent selected    from the group consisting of alkyl, alkenyl, alkynyl, halo,    haloalkyl, haloalkenyl, haloalkynyl, oxo, optionally substituted    aryl, optionally substituted aralkyl, optionally substituted    aralkenyl, optionally substituted aralkynyl, optionally substituted    cycloalkyl, optionally substituted cycloalkylalkyl, optionally    substituted cycloalkylalkenyl, optionally substituted    cycloalkylalkynyl, optionally substituted heterocyclyl, optionally    substituted heterocyclylalkyl, optionally substituted    heterocyclylalkenyl, optionally substituted heterocyclylalkynyl,    optionally substituted heteroaryl, optionally substituted    heteroarylalkyl, optionally substituted heteroarylalkenyl,    optionally substituted heteroarylalkynyl, —R⁸—OR⁶, —R⁸—C(O)R⁶,    —R⁸—C(O)OR⁶, —R⁹—N(R⁶)R⁷, —R⁸—C(O)N(R⁶)R⁷, —R⁸—S(O)₂N(R⁶)R⁷, and    —R⁸—S(O)_(p)R⁶ (where p is 0, 1 or 2);-   each R⁶ and each R⁷ is independently selected from the group    consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl,    haloalkenyl, haloalkynyl, optionally substituted cycloalkyl,    optionally substituted cycloalkylalkyl, optionally substituted aryl,    optionally substituted aralkyl, optionally substituted aralkenyl,    optionally substituted aralkynyl, optionally substituted    heterocyclyl, optionally substituted heterocyclylalkyl, optionally    substituted heterocyclylalkenyl, optionally substituted    heterocyclylalkynyl, optionally substituted heteroaryl, optionally    substituted heteroarylalkyl, optionally substituted    heteroarylalkenyl, and optionally substituted heteroarylalkynyl; or    any R⁶ and R⁷, together with the common nitrogen to which they are    both attached, form an optionally substituted N-heteroaryl or an    optionally substituted N-heterocyclyl;-   each R⁸ is independently selected from the group consisting of a    direct bond, an optionally substituted straight or branched alkylene    chain, an optionally substituted straight or branched alkenylene    chain and an optionally substituted straight or branched alkynylene    chain; and-   each R⁹ is independently selected from the group consisting of an    optionally substituted straight or branched alkylene chain, an    optionally substituted straight or branched alkenylene chain and an    optionally substituted straight or branched alkynylene chain;-   provided at least one of R⁵ and a substituent on R⁴ is a bridged    N-heterocyclyl;    as an isolated stereoisomer or a mixture thereof and when comprising    one or more stereoisomeric substituents.

In another aspect, this invention is directed to pharmaceuticalcompositions comprising a pharmaceutically acceptable excipient and acompound of the invention, as described herein, as an isolatedstereoisomer or mixture thereof, or a pharmaceutically acceptable saltthereof.

In another aspect, this invention is directed to methods of treating adisease or condition associated with JAK activity in a mammal,particularly JAK2, wherein the methods comprise administering to themammal a therapeutically effective amount of a compound of theinvention, as described above, as an isolated stereoisomer or mixturethereof, or a pharmaceutically acceptable salt thereof, or atherapeutically effective amount of a pharmaceutical compositioncomprising a pharmaceutically acceptable excipient and a compound of theinvention, as described herein, as an isolated stereoisomer or mixturethereof, or a pharmaceutically acceptable salt thereof.

In another aspect, this invention provides assays to determine theeffectiveness of a compound of the invention in inhibiting JAK activity,particularly JAK2 activity, in a cell-based assay.

In another aspect, this invention provides a method of inhibiting anactivity of a JAK kinase comprising contacting the JAK kinase with anamount of a compound effective to inhibit an activity of the JAK kinase,wherein the compound is selected from the compounds of this invention,or pharmaceutically acceptable salts thereof, as described herein.

In another aspect, this invention provides a method of inhibiting anactivity of a JAK kinase comprising contacting in vitro a JAK2 kinasewith an amount of a compound effective to inhibit an activity of the JAKkinase, wherein the compound is selected from the compounds of thisinvention, or pharmaceutically acceptable salts thereof, as describedherein.

In another aspect, this invention provides a method of inhibiting anactivity of a JAK kinase comprising contacting in a cell a JAK2 kinasewith an amount of a compound effective to inhibit an activity of theJAK2 kinase, wherein the compound is selected from the compounds of thisinvention, or pharmaceutically acceptable salts thereof, as describedherein.

In another aspect, this invention provides a method of treating a T-cellmediated autoimmune disease comprising administering to a patientsuffering from such an autoimmune disease an amount of a compoundeffective to treat the autoimmune disease, wherein the compound isselected from the compounds of this invention, or pharmaceuticallyacceptable salts thereof, as described herein.

In another aspect, this invention provides a method of treatingallograft transplant rejection in a mammal, preferably a transplantrecipient, comprising administering to the mammal a therapeuticallyeffective amount of a compound of the invention, or a pharmaceuticallyacceptable salt thereof, as described herein.

In another aspect, this invention provides a method of treating a TypeIV hypersensitivity reaction in a mammal comprising administering to themammal in need thereof a therapeutically effective amount of a compoundof the invention, or a pharmaceutically acceptable salt thereof, asdescribed herein.

In another aspect, this invention provides a method of inhibiting asignal transduction cascade in which JAK2 kinase plays a role comprisingcontacting a cell expressing a receptor involved in such a signalingcascade with an inhibitory amount of a compound of the invention, or apharmaceutically acceptable salt thereof, as described herein.

In another aspect, this invention provides a method of treating a JAKkinase-mediated disease or condition in a mammal comprisingadministering to the mammal in need thereof a therapeutically effectiveamount of a compound of the invention, or a pharmaceutically acceptablesalt thereof, as described herein.

In another aspect, this invention provides a method of treating a JAK2kinase-mediated myeloproliferative disorder (MPD), such as polycythemiavera (PV), essential thrombocythemia (ET) and primary myelofibrosis(PMF) or JAK-dependent malignancies in a mammal, comprisingadministering to the mammal in need thereof a therapeutically effectiveamount of a compound of the invention, or a pharmaceutically acceptablesalt thereof, as described herein.

In another aspect, this invention provides a kit comprising a compoundselected from the compounds of this invention, or pharmaceuticallyacceptable salts thereof, packaging, and instructions for use.

DETAILED DESCRIPTION OF THE INVENTION Definitions

As used in the specification and appended claims, unless specified tothe contrary, the following terms have the meaning indicated:

“Ring A” refers to

in compounds of formula (I), as described above in the Summary of theInvention.

“Amino” refers to the —NH₂ radical.

“Carboxy” refers to the —C(O)OH radical.

“Cyano” refers to the —CN radical.

“Nitro” refers to the —NO₂ radical.

“Oxa” refers to the —O— radical.

“Oxo” refers to the ═O radical.

“Thioxo” refers to the ═S radical.

“Alkyl” refers to a fully saturated, straight or branched hydrocarbonchain radical consisting solely of carbon and hydrogen atoms, havingfrom one to twelve carbon atoms, one to eight carbon atoms or one to sixcarbon atoms and which is attached to the rest of a molecule by a singlebond, for example, methyl, ethyl, n-propyl, 1-methylethyl(iso-propyl),n-butyl, n-pentyl, 1,1-dimethylethyl(t-butyl), 3-methylhexyl,2-methylhexyl, and the like. For purposes of this invention, the term“lower alkyl” refers to an alkyl radical having one to six carbon atoms.

“Optionally substituted alkyl” refers to an alkyl radical, as definedabove, which is optionally substituted by one or more substituentsselected from the group consisting of halo, cyano, nitro, oxo, thioxo,trimethylsilanyl, —OR²⁰, —OC(O)—R²⁰, —N(R²⁰)₂, —C(O)R²⁰, —C(O)OR²⁰,—C(O)N(R²⁰)₂, —N(R²⁰)C(O)OR²⁰, —N(R²⁰)C(O)R²⁰, —N(R²⁰)S(O)₂R²⁰,—S(O)_(t)OR²⁰ (where t is 1 or 2), —S(O)_(p)R²⁰ (where p is 0, 1 or 2),and —S(O)₂N(R²⁰)₂ where each R²⁰ is independently selected from thegroup consisting of hydrogen, alkyl, haloalkyl, optionally substitutedcycloalkyl, optionally substituted cycloalkylalkyl, optionallysubstituted aryl, optionally substituted aralkyl, optionally substitutedheterocyclyl, optionally substituted heterocyclylalkyl, optionallysubstituted heteroaryl and optionally substituted heteroarylalkyl, ortwo R²⁰'s, together with the common nitrogen to which they are bothattached, form an optionally substituted N-heterocyclyl or an optionallysubstituted N-heteroaryl.

“Alkenyl” refers to a straight or branched hydrocarbon chain radicalconsisting solely of carbon and hydrogen atoms, containing at least onedouble bond, having from one to twelve carbon atoms, or one to eightcarbon atoms, and which is attached to the rest of a molecule by asingle bond or a double bond, for example, ethenyl, prop-1-enyl,but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like.

“Optionally substituted alkenyl” refers to an alkenyl radical, asdefined above, which is optionally substituted by one or moresubstituents selected from the group consisting of halo, cyano, nitro,oxo, thioxo, trimethylsilanyl, —OR²⁰, —OC(O)—R²⁰, —N(R²⁰)₂, —C(O)R²⁰,—C(O)OR²⁰, —C(O)N(R²⁰)₂, —N(R²⁰)C(O)OR²⁰, —N(R²⁰)C(O)R²⁰,—N(R²⁰)S(O)₂R²⁰, —S(O)_(t)OR²⁰ (where t is 1 or 2), —S(O)_(p)R²⁰ (wherep is 0, 1 or 2), and —S(O)₂N(R²⁰)₂ where each R²⁰ is independentlyselected from the group consisting of hydrogen, alkyl, haloalkyl,optionally substituted cycloalkyl, optionally substitutedcycloalkylalkyl, optionally substituted aryl, optionally substitutedaralkyl, optionally substituted heterocyclyl, optionally substitutedheterocyclylalkyl, optionally substituted heteroaryl and optionallysubstituted heteroarylalkyl, or two R²⁰'s, together with the commonnitrogen to which they are both attached, form an optionally substitutedN-heterocyclyl or an optionally substituted N-heteroaryl.

“Alkynyl” refers to a straight or branched hydrocarbon chain radicalconsisting solely of carbon and hydrogen atoms, containing at least onetriple bond, optionally containing at least one double bond, having fromtwo to twelve carbon atoms, or two to eight carbon atoms, and which isattached to the rest of a molecule by a single bond or a double bond,for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and thelike.

“Optionally substituted alkynyl” refers to an alkynyl radical, asdefined above, which is optionally substituted by one or moresubstituents selected from the group consisting of halo, cyano, nitro,oxo, thioxo, trimethylsilanyl, —OR²⁰, —OC(O)—R²⁰, —N(R²⁰)₂, —C(O)R²⁰,—C(O)OR²⁰, —C(O)N(R²⁰)₂, —N(R²⁰)C(O)OR²⁰, —N(R²⁰)C(O)R²⁰,—N(R²⁰)S(O)₂R²⁰, —S(O)_(t)OR²⁰ (where t is 1 or 2), —S(O)_(p)R²⁰ (wherep is 0, 1 or 2), and —S(O)₂N(R²⁰)₂ where each R²⁰ is independentlyselected from the group consisting of hydrogen, alkyl, haloalkyl,optionally substituted cycloalkyl, optionally substitutedcycloalkylalkyl, optionally substituted aryl, optionally substitutedaralkyl, optionally substituted heterocyclyl, optionally substitutedheterocyclylalkyl, optionally substituted heteroaryl and optionallysubstituted heteroarylalkyl, or two R²⁰'s, together with the commonnitrogen to which they are both attached, form an optionally substitutedN-heterocyclyl or an optionally substituted N-heteroaryl.

“Straight or branched alkylene chain” refers to a straight or brancheddivalent hydrocarbon chain linking the rest of a molecule to a radicalgroup, consisting solely of carbon and hydrogen, containing nounsaturation and having from one to twelve carbon atoms, for example,methylene, ethylene, propylene, n-butylene, and the like. The alkylenechain is attached to the rest of a molecule through a single bond and tothe radical group through a single bond. The points of attachment of thealkylene chain to the rest of a molecule and to the radical group can bethrough one carbon in the alkylene chain or through any two carbonswithin the chain.

“Optionally substituted straight or branched alkylene chain” refers toan alkylene chain, as defined above, which is optionally substituted byone or more substituents selected from the group consisting of halo,cyano, nitro, aryl, cycloalkyl, heterocyclyl, heteroaryl, oxo, thioxo,trimethylsilanyl, —OR²⁰, —OC(O)—R²⁰, —N(R²⁰)₂, —C(O)R²⁰, —C(O)OR²⁰,—C(O)N(R²⁰)₂, —N(R²⁰)C(O)OR²⁰, —N(R²⁰)C(O)R²⁰, —N(R²⁰)S(O)₂R²⁰,—S(O)_(t)OR²⁰ (where t is 1 or 2), —S(O)_(p)R²⁰ (where p is 0, 1 or 2),and —S(O)₂N(R²⁰)₂ where each R²⁰ is independently selected from thegroup consisting of hydrogen, alkyl, haloalkyl, optionally substitutedcycloalkyl, optionally substituted cycloalkylalkyl, optionallysubstituted aryl, optionally substituted aralkyl, optionally substitutedheterocyclyl, optionally substituted heterocyclylalkyl, optionallysubstituted heteroaryl and optionally substituted heteroarylalkyl, ortwo R²⁰'s, together with the common nitrogen to which they are bothattached, form an optionally substituted N-heterocyclyl or an optionallysubstituted N-heteroaryl.

“Straight or branched alkenylene chain” refers to a straight or brancheddivalent hydrocarbon chain linking the rest of a molecule to a radicalgroup, consisting solely of carbon and hydrogen, containing at least onedouble bond and having from one to twelve carbon atoms, for example,ethenylene, propenylene, n-butenylene, and the like. The alkenylenechain is attached to the rest of a molecule through a double bond or asingle bond and to the radical group through a double bond or a singlebond. The points of attachment of the alkenylene chain to the rest ofthe molecule and to the radical group can be through one carbon or anytwo carbons within the chain.

“Optionally substituted straight or branched alkenylene chain” refers toan alkenylene chain, as defined above, which is optionally substitutedby one or more substituents selected from the group consisting of halo,cyano, nitro, aryl, cycloalkyl, heterocyclyl, heteroaryl, oxo, thioxo,trimethylsilanyl, —OR²⁰, —OC(O)—R²⁰, —N(R²⁰)₂, —C(O)R²⁰, —C(O)OR²⁰,—C(O)N(R²⁰)₂, —N(R²⁰)C(O)OR²⁰, —N(R²⁰)C(O)R²⁰, —N(R²⁰)S(O)₂R²⁰,—S(O)_(t)OR²⁰ (where t is 1 or 2), —S(O)_(p)R²⁰ (where p is 0, 1 or 2),and —S(O)₂N(R²⁰)₂ where each R²⁰ is independently selected from thegroup consisting of hydrogen, alkyl, haloalkyl, optionally substitutedcycloalkyl, optionally substituted cycloalkylalkyl, optionallysubstituted aryl, optionally substituted aralkyl, optionally substitutedheterocyclyl, optionally substituted heterocyclylalkyl, optionallysubstituted heteroaryl and optionally substituted heteroarylalkyl, ortwo R²⁰'s, together with the common nitrogen to which they are bothattached, form an optionally substituted N-heterocyclyl or an optionallysubstituted N-heteroaryl.

“Straight or branched alkynylene chain” refers to a straight or brancheddivalent hydrocarbon chain linking the rest of a molecule to a radicalgroup, consisting solely of carbon and hydrogen, containing at least onetriple bond and having from two to twelve carbon atoms, for example,propynylene, n-butynylene, and the like. The alkynylene chain isattached to the rest of a molecule through a single bond and to theradical group through a double bond or a single bond. The points ofattachment of the alkynylene chain to the rest of a molecule and to theradical group can be through one carbon or any two carbons within thechain.

“Optionally substituted straight or branched alkynylene chain” refers toan alkynylene chain, as defined above, which is optionally substitutedby one or more substituents selected from the group consisting of alkyl,alkenyl, halo, haloalkenyl, cyano, nitro, aryl, cycloalkyl,heterocyclyl, heteroaryl, oxo, thioxo, trimethylsilanyl, —OR²⁰,—OC(O)—R²⁰, —N(R²⁰)₂, —C(O)R²⁰, —C(O)OR²⁰, —C(O)N(R²⁰)₂,—N(R²⁰)C(O)OR²⁰, —N(R²⁰)C(O)R²⁰, —N(R²⁰)S(O)₂R²⁰, —S(O)_(t)OR²⁰ (where tis 1 or 2), —S(O)_(p)R²⁰ (where p is 0, 1 or 2), and —S(O)₂N(R²⁰)₂ whereeach R²⁰ is independently selected from the group consisting ofhydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl,optionally substituted cycloalkylalkyl, optionally substituted aryl,optionally substituted aralkyl, optionally substituted heterocyclyl,optionally substituted heterocyclylalkyl, optionally substitutedheteroaryl and optionally substituted heteroarylalkyl, or two R²⁰'s,together with the common nitrogen to which they are both attached, forman optionally substituted N-heterocyclyl or an optionally substitutedN-heteroaryl.

“Aryl” refers to a hydrocarbon ring system radical comprising hydrogen,6 to 14 carbon atoms and at least one aromatic ring. For purposes ofthis invention, the aryl radical may be a monocyclic, bicyclic, ortricyclic system and which may include spiro ring systems. An arylradical is commonly, but not necessarily, attached to a parent moleculevia an aromatic ring of the aryl radical. Aryl radicals include, but arenot limited to, aryl radicals derived from acenaphthylene, anthracene,azulene, benzene, 6,7,8,9-tetrahydro-5H-benzo[7]annulene, fluorene,as-indacene, s-indacene, indane, indene, naphthalene, phenalene, andphenanthrene.

“Optionally substituted aryl” refers to an aryl radical, as definedabove, which is optionally substituted by one or more substituentsselected from the group consisting of alkyl, alkenyl, alkynyl, halo,haloalkyl, haloalkenyl, haloalkynyl, cyano, nitro, optionallysubstituted aryl, optionally substituted aralkyl, optionally substitutedaralkenyl, optionally substituted aralkynyl, optionally substitutedcycloalkyl, optionally substituted cycloalkylalkyl, optionallysubstituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl,optionally substituted heterocyclyl, optionally substitutedheterocyclylalkyl, optionally substituted heterocyclylalkenyl,optionally substituted heterocyclylalkynyl, optionally substitutedheteroaryl, optionally substituted heteroarylalkyl, optionallysubstituted heteroarylalkenyl, optionally substituted heteroarylalkynyl,—R²¹—OR²⁰, —R²¹—OC(O)—R²⁰, —R²¹—N(R²⁰)₂, —R²¹—C(O)R²⁰, —R²¹—C(O)OR²⁰,—R²¹—C(O)N(R²⁰)₂, —R²¹—O—R²²—C(O)N(R²⁰)₂, —R²¹—N(R²⁰)C(O)OR²⁰,—R²¹—N(R²⁰)C(O)R²⁰, —R²¹—N(R²⁰)S(O)₂R²⁰, —R²¹—C(═NR²⁰)N(R²⁰)₂,—R²¹—S(O)_(t)OR²⁰ (where t is 1 or 2), —R²¹—S(O)_(p)R²⁰ (where p is 0, 1or 2), and —R²¹—S(O)₂N(R²⁰)₂, where each R²⁰ is independently selectedfrom the group consisting of hydrogen, alkyl, haloalkyl, optionallysubstituted cycloalkyl, optionally substituted cycloalkylalkyl,optionally substituted aryl, optionally substituted aralkyl, optionallysubstituted heterocyclyl, optionally substituted heterocyclylalkyl,optionally substituted heteroaryl and optionally substitutedheteroarylalkyl, or two R²⁰'s, together with the common nitrogen towhich they are both attached, form an optionally substitutedN-heterocyclyl or an optionally substituted N-heteroaryl, each R²¹ isindependently a direct bond or a straight or branched alkylene oralkenylene chain, and R²² is a straight or branched alkylene oralkenylene chain.

“Aralkyl” refers to a radical of the formula —R_(b)—R_(c) where R_(b) isan alkylene chain as defined above and R_(c) is one or more arylradicals as defined above, for example, benzyl, diphenylmethyl and thelike.

“Optionally substituted aralkyl” refers to an aralkyl radical, asdefined above, wherein the alkylene chain of the aralkyl radical is anoptionally substituted alkylene chain, as defined above, and each arylradical of the aralkyl radical is an optionally substituted arylradical, as defined above.

“Aralkenyl” refers to a radical of the formula —R_(d)—R_(c) where R_(d)is an alkenylene chain as defined above and R_(c) is one or more arylradicals as defined above.

“Optionally substituted aralkenyl” refers to an aralkenyl radical, asdefined above, wherein the alkenylene chain of the aralkenyl radical isan optionally substituted alkenylene chain, as defined above, and eacharyl radical of the aralkenyl radical is an optionally substituted arylradical, as defined above.

“Aralkynyl” refers to a radical of the formula —R_(e)R_(c), where R_(e)is an alkynylene chain as defined above and R_(c) is one or more arylradicals as defined above.

“Optionally substituted aralkynyl” refers to an aralkynyl radical, asdefined above, wherein the alkynylene chain of the aralkynyl radical isan optionally substituted alkynylene chain, as defined above, and eacharyl radical of the aralkynyl radical is an optionally substituted arylradical, as defined above.

“Cycloalkyl” refers to a stable non-aromatic monocyclic or polycyclichydrocarbon radical consisting solely of carbon and hydrogen atoms,which includes fused, spiro or bridged ring systems, having from threeto fifteen carbon atoms, or having from three to ten carbon atoms, orfrom five to seven carbons and which is saturated or unsaturated andattached to the rest of a molecule by a single bond. For purposes ofthis invention, a bridged ring system is a system wherein twonon-adjacent ring atoms thereof are connected through an atom or a groupof atoms, wherein the atom or the group of atoms are the bridgingelement. An example of a bridged cycloalkyl (monovalent) radical isnorbornanyl (also called bicyclo[2.2.1]heptanyl). For purposes of thisinvention, a non-bridged ring system is a system which does not containa bridging element, as described above. For purposes of this invention,a fused ring system is a system wherein two adjacent ring atoms thereofare connected through an atom or a group of atoms. An example of a fusedcycloalkyl (monovalent) radical is decahydronaphthalenyl (also calleddecalinyl). For purposes of this invention, a spiro ring system is asystem wherein two rings are joined via a single carbon (quaternary)atom. An example of a spiro cycloalkyl (monovalent) radical isspiro[5.5]undecanyl. Monocyclic cycloalkyl radicals do not includespiro, fused or bridged cycloalkyl radicals, but do include for example,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, andcyclooctyl. Polycyclic radicals include fused, spiro or bridgedcycloalkyl radicals, for example, C₁₀ radicals such as adamantanyl(bridged) and decalinyl (fused), and C₇ radicals such asbicyclo[3.2.0]heptanyl (fused), norbornanyl and norbornenyl (bridged),as well as substituted polycyclic radicals, for example, substituted C₇radicals such as 7,7-dimethylbicyclo[2.2.1]heptanyl (bridged), and thelike.

“Optionally substituted cycloalkyl” refers to a cycloalkyl radical, asdefined above, which is optionally substituted by one or moresubstituents selected from the group consisting of alkyl, alkenyl,alkynyl, halo, haloalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano,nitro, optionally substituted aryl, optionally substituted aralkyl,optionally substituted aralkenyl, optionally substituted aralkynyl,optionally substituted cycloalkyl, cycloalkylalkyl, optionallysubstituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl,optionally substituted heterocyclyl, optionally substitutedheterocyclylalkyl, optionally substituted heterocyclylalkenyl,optionally substituted heterocyclylalkynyl, optionally substitutedheteroaryl, optionally substituted heteroarylalkyl, optionallysubstituted heteroarylalkenyl, optionally substituted heteroarylalkynyl,—R²¹—OR²⁰, —R²¹—OC(O)—R²⁰, —R²¹—N(R²⁰)₂, —R²¹—C(O)R²⁰, —R²¹—C(O)OR²⁰,—R²¹—C(O)N(R²⁰)₂, —R²¹—N(R²⁰)C(O)OR²⁰, —R²¹—N(R²⁰)C(O)R²⁰,—R²¹—N(R²⁰)S(O)₂R²⁰, —R²¹—C(═NR²⁰)N(R²⁰)₂, —R²¹—S(O)_(t)OR²⁰ (where t is1 or 2), —R²¹—S(O)_(p)R²⁰ (where p is 0, 1 or 2), and —R²¹—S(O)₂N(R²⁰)₂,where each R²⁰ is independently selected from the group consisting ofhydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl,optionally substituted cycloalkylalkyl, optionally substituted aryl,optionally substituted aralkyl, optionally substituted heterocyclyl,optionally substituted heterocyclylalkyl, optionally substitutedheteroaryl and optionally substituted heteroarylalkyl, or two R²⁰'s,together with the common nitrogen to which they are both attached, forman optionally substituted N-heterocyclyl or an optionally substitutedN-heteroaryl, and each R²¹ is independently a direct bond or a straightor branched alkylene or alkenylene chain.

“Cycloalkylalkyl” refers to a radical of the formula —R_(b)R_(g) whereR_(b) is an alkylene chain as defined above and R_(g) is a cycloalkylradical as defined above.

“Optionally substituted cycloalkylalkyl” refers to a cycloalkylalkylradical, as defined above, wherein the alkylene chain of thecycloalkylalkyl radical is an optionally substituted alkylene chain, asdefined above, and the cycloalkyl radical of the cycloalkylalkyl radicalis an optionally substituted cycloalkyl radical, as defined above.

“Cycloalkylalkenyl” refers to a radical of the formula —R_(d)R_(g) whereR_(d) is an alkenylene chain as defined above and R_(g) is a cycloalkylradical as defined above.

“Optionally substituted cycloalkylalkenyl” refers to a cycloalkylalkenylradical, as defined above, wherein the alkenylene chain of thecycloalkylalkenyl radical is an optionally substituted alkenylene chain,as defined above, and the cycloalkyl radical of the cycloalkylalkenylradical is an optionally substituted cycloalkyl radical as definedabove.

“Cycloalkylalkynyl” refers to a radical of the formula —R_(e)R_(g) whereR_(e) is an alkynylene radical as defined above and R_(g) is acycloalkyl radical as defined above.

“Optionally substituted cycloalkylalkynyl” refers to a cycloalkylalkynylradical, as defined above, wherein the alkynylene chain of thecycloalkylalkynyl radical is an optionally substituted alkynylene chain,as defined above, and the cycloalkyl radical of the cycloalkylalkynylradical is an optionally substituted cycloalkyl radical as definedabove.

“Halo” refers to bromo, chloro, fluoro or iodo.

“Haloalkyl” refers to an alkyl radical, as defined above, that issubstituted by one or more halo radicals, as defined above, for example,trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl,1-fluoromethyl-2-fluoroethyl, 3-bromo-2-fluoropropyl,1-bromomethyl-2-bromoethyl, and the like.

“Haloalkenyl” refers to an alkenyl radical, as defined above, that issubstituted by one or more halo radicals, as defined above.

“Haloalkynyl” refers to an alkynyl radical, as defined above, that issubstituted by one or more halo radicals, as defined above.

“Heterocyclyl” refers to a stable 3- to 18-membered non-aromatic ringsystem radical which comprises one to twelve carbon atoms and from oneto six heteroatoms selected from the group consisting of nitrogen,oxygen and sulfur. Unless stated otherwise specifically in thespecification, the heterocyclyl radical may be a monocyclic, bicyclic,tricyclic or tetracyclic ring system, which may include spiro or bridgedring systems; and the nitrogen, carbon or sulfur atoms in theheterocyclyl radical may be optionally oxidized; the nitrogen atom maybe optionally quaternized; and the heterocyclyl radical may be partiallyor fully saturated. Examples of a bridged heterocyclyl include, but arenot limited to, azabicyclo[2.2.1]heptanyl, diazabicyclo[2.2.1]heptanyl,oxazabicyclo[2.2.1]heptanyl, diazabicyclo[2.2.2]octanyl,azabicyclo[3.2.1]octanyl, diazabicyclo[3.2.1]octanyl,azabicyclo[3.3.1]nonanyl, diazabicyclo[3.3.1]nonanyl,azabicyclo[3.2.2.]nonanyl, diazabicyclo[3.2.2]nonanyl,6,9-methanooctahydropyrido[1,2-a]pyrazinyl, azabicyclo[3.3.2]decanyl anddiazabicyclo[3.3.2]decanyl. A “bridged N-heterocyclyl” is a bridgedheterocyclyl containing at least one nitrogen, but which optionallycontains up to four additional heteroatoms selected from O, N and S. Forpurposes of this invention, a non-bridged ring system is a systemwherein no two non-adjacent ring atoms thereof are connected through anatom or a group of atoms. Examples of heterocyclyl radicals include, butare not limited to, dioxolanyl, 1,4-diazepanyl, decahydroisoquinolyl,imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl,morpholinyl, octahydroindolyl, octahydroisoindolyl,octahydro-1H-pyrrolo[3,2-c]pyridinyl,octahydro-1H-pyrrolo[2,3-d]pyridinyl,octahydro-1H-pyrrolo[2,3-b]pyridinyl,octahydro-1H-pyrrolo[3,4-b]pyridinyl, octahydropyrrolo[3,4-c]pyrrolyl,octahydro-1H-pyrido[1,2-a]pyrazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl,2-oxopyrrolidinyl, oxazolidinyl, 3,7-diazabicyclo[3.3.1]nonan-3-yl,piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl,quinuclidinyl, thiazolidinyl, tetrahydrofuranyl, thienyl[1,3]dithianyl,trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl,1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, azetidinyl,octahydropyrrolo[3,4-c]pyrrolyl, octahydropyrrolo[3,4-b]pyrrolyl,decahydroprazino[1,2-a]azepinyl, azepanyl, azabicyclo[3.2.1]octyl, and2,7-diazaspiro[4.4]nonanyl.

“Optionally substituted heterocyclyl” refers to a heterocyclyl radical,as defined above, which is optionally substituted by one or moresubstituents selected from the group consisting of alkyl, alkenyl,alkynyl, halo, haloalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano,nitro, optionally substituted aryl, optionally substituted aralkyl,optionally substituted aralkenyl, optionally substituted aralkynyl,optionally substituted cycloalkyl, optionally substitutedcycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionallysubstituted cycloalkylalkynyl, optionally substituted heterocyclyl,optionally substituted heterocyclylalkyl, optionally substitutedheterocyclylalkenyl, optionally substituted heterocyclylalkynyl,optionally substituted heteroaryl, optionally substitutedheteroarylalkyl, optionally substituted heteroarylalkenyl, optionallysubstituted heteroarylalkynyl, —R²¹—OR²⁰, —R²¹—OC(O)—R²⁰, —R²¹—N(R²⁰)₂,—R²¹—C(O)R²⁰, —R²¹—C(O)OR²⁰, —R²¹—C(O)N(R²⁰)₂, —R²¹—N(R²⁰)C(O)OR²⁰,—R²¹—N(R²⁰)C(O)R²⁰, —R²¹—N(R²⁰)S(O)₂R²⁰, —R²¹—C(═NR²⁰)N(R²⁰)₂,—R²¹—S(O)_(t)OR²⁰ (where t is 1 or 2), —R²¹—S(O)_(p)R²⁰ (where p is 0, 1or 2), and —R²¹—S(O)₂N(R²⁰)₂, where each R²⁰ is independently selectedfrom the group consisting of hydrogen, alkyl, haloalkyl, optionallysubstituted cycloalkyl, optionally substituted cycloalkylalkyl,optionally substituted aryl, optionally substituted aralkyl, optionallysubstituted heterocyclyl, optionally substituted heterocyclylalkyl,optionally substituted heteroaryl and optionally substitutedheteroarylalkyl, or two R²⁰'s, together with the common nitrogen towhich they are both attached, form an optionally substitutedN-heterocyclyl or an optionally substituted N-heteroaryl, and each R²¹is independently a direct bond or a straight or branched alkylene oralkenylene chain.

“N-heterocyclyl” refers to a heterocyclyl radical as defined abovecontaining at least one nitrogen and where the point of attachment ofthe N-heterocyclyl radical to the rest of a molecule may be through anitrogen atom in the N-heterocyclyl radical or through a carbon in theN-heterocyclyl radical.

“Optionally substituted N-heterocyclyl” refers to an N-heterocyclyl, asdefined above, which is optionally substituted by one or moresubstituents as defined above for optionally substituted heterocyclyl.

“Heterocyclylalkyl” refers to a radical of the formula —R_(b)R_(h) whereR_(b) is an alkylene chain as defined above and R_(h) is a heterocyclylradical as defined above, and when the heterocyclyl is anitrogen-containing heterocyclyl, the heterocyclyl may be attached tothe alkylene chain at the nitrogen atom.

“Optionally substituted heterocyclylalkyl” refers to a heterocyclylalkylradical, as defined above, wherein the alkylene chain of theheterocyclylalkyl radical is an optionally substituted alkylene chain,as defined above, and the heterocyclyl radical of the heterocyclylalkylradical is an optionally substituted heterocyclyl radical, as definedabove.

“Heterocyclylalkenyl” refers to a radical of the formula —R_(d)R_(h)where R_(d) is an alkenylene chain as defined above and R_(h) is aheterocyclyl radical as defined above, and when the heterocyclyl is anitrogen-containing heterocyclyl, the heterocyclyl may be attached tothe alkenylene chain at the nitrogen atom.

“Optionally substituted heterocyclylalkenyl” refers to aheterocyclylalkenyl radical, as defined above, wherein the alkenylenechain of the heterocyclylalkenyl radical is an optionally substitutedalkenylene chain, as defined above, and the heterocyclyl radical of theheterocyclylalkenyl radical is an optionally substituted heterocyclylradical, as defined above.

“Heterocyclylalkynyl” refers to a radical of the formula —R_(e)R_(h)where R_(e) is an alkynylene chain as defined above and R_(h) is aheterocyclyl radical as defined above, and when the heterocyclyl is anitrogen-containing heterocyclyl, the heterocyclyl may be attached tothe alkynylene chain at the nitrogen atom.

“Optionally substituted heterocyclylalkynyl” refers to aheterocyclylalkynyl radical, as defined above, wherein the alkynylenechain of the heterocyclylalkynyl radical is an optionally substitutedalkynylene chain, as defined above, and the heterocyclyl radical of theheterocyclylalkynyl radical is an optionally substituted heterocyclylradical, as defined above.

“Heteroaryl” refers to a 5- to 14-membered ring system radicalcomprising hydrogen atoms, one to thirteen carbon atoms, one to sixheteroatoms selected from the group consisting of nitrogen, oxygen andsulfur, and at least one aromatic ring. A heteroaryl radical iscommonly, but not necessarily, attached to the parent molecule via anaromatic ring of the heteroaryl radical. For purposes of this invention,the heteroaryl radical may be a monocyclic, bicyclic or tricyclic ringsystem, which may include spiro or bridged ring systems; and thenitrogen, carbon or sulfur atoms in the heteroaryl radical may beoptionally oxidized and the nitrogen atom may be optionally quaternized.For purposes of this invention, the aromatic ring of the heteroarylradical need not contain a heteroatom, as long as one ring of theheteroaryl radical contains a heteroatom. For example benzo-fusedheterocyclyls, like 1,2,3,4-tetrahydroisoquinolin-7-yl, are considered a“heteroaryl” for the purposes of this invention. Examples of heteroarylradicals include, but are not limited to, azepinyl, acridinyl,benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl,benzoxazolyl, benzothiazolyl, benzothiadiazolyl,benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, benzo[b]azepinyl,2,3,4,5-tetrahydro-1H-benzo[b]azepinyl, 1,4-benzodioxanyl,benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl,benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl(benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl,benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl,cyclopenta[d]pyrimidinyl, 3,4-dihydro-2H-benzo[b][1,4]dioxepinyl,cyclopenta[4,5]thieno[2,3-d]pyrimidinyl such as6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl,5,6-dihydrobenzo[h]quinazolinyl, 3,4-dihydro-2H-benzo[b][1,4]thiazinyl,5,6-dihydrobenzo[h]cinnolinyl,7′,8′-dihydro-5′H-spiro[[1,3]dioxolane-2,6′-quinoline]-3′-yl,6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl,2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazinyl,3′,4′-dihydrospiro[cyclobutane-1,2′-pyrido[3,2-b][1,4]oxazinyl,dihydropyridooxazinyl such as 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl,dihydropyridothiazinyl such as3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazinyl, dibenzofuranyl,dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl,furopyrimidinyl, furopyridazinyl, furopyrazinyl, isothiazolyl,imidazolyl, imidazopyrimidinyl, imidazopyridazinyl, imidazopyrazinyl,imidazo[1,2-a]pyridinyl, indazolyl, indolyl, indazolyl, isoindolyl,indolinyl, isoindolinyl, isoquinolinyl (isoquinolyl), indolizinyl,isoxazolyl, naphthyridinyl, 1,6-naphthyridinonyl, oxadiazolyl,2-oxoazepinyl, oxazolyl, oxiranyl,5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl,3′-oxo-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrido[3,2-b][1,4]oxazine]yl,7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridinyl, 1-phenyl-1H-pyrrolyl,phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, phenanthridinyl,pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl,pyridinyl (pyridyl), pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl,pyrazinyl, pyrimidinyl, pyridazinyl (pyridazyl), pyrrolyl,pyrrolopyrimidinyl, pyrrolopyridazinyl, pyrrolopyrazinyl,2H-pyrido[3,2-b][1,4]oxazinonyl, 1H-pyrido[2,3-b][1,4]oxazinonyl,pyrrolopyridinyl such as 1H-pyrrolo[2,3-b]pyridinyl, quinazolinyl,quinoxalinyl, quinolinyl, quinuclidinyl, tetrahydroquinolinyl,5,6,7,8-tetrahydroquinazolinyl, 2,3,4,5-tetrahydrobenzo[b]oxepinyl,6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indolyl,6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridinyl,6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepinyl,5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl,6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl,5,6,7,8-tetrahydropyrido[4,5-d]pyridazinyl,7,8,9,9a-tetrahydro-5H-pyrido[2,3-e]pyrrolo[1,2-a][1,4]diazepin-10(11H)-onyl,thiazolyl, thiadiazolyl, triazolyl, tetrazolyl,1,2,3,4-tetrahydroisoquinolin-7-yl, triazinyl, thieno[2,3-d]pyrimidinyl,thienopyrimidinyl (e.g., thieno[3,2-d]pyrimidinyl),thieno[2,3-c]pyridinyl, thienopyridazinyl, thienopyrazinyl, andthiophenyl (thienyl).

“Optionally substituted heteroaryl” refers to a heteroaryl radical, asdefined above, which is optionally substituted by one or moresubstituents selected from the group consisting of alkyl, alkenyl,alkynyl, halo, haloalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano,nitro, optionally substituted aryl, optionally substituted aralkyl,optionally substituted aralkenyl, optionally substituted aralkynyl,optionally substituted cycloalkyl, optionally substitutedcycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionallysubstituted cycloalkylalkynyl, optionally substituted heterocyclyl,optionally substituted heterocyclylalkyl, optionally substitutedheterocyclylalkenyl, optionally substituted heterocyclylalkynyl,optionally substituted heteroaryl, optionally substitutedheteroarylalkyl, optionally substituted heteroarylalkenyl, optionallysubstituted heteroarylalkynyl, —R²¹—OR²⁰, —R²¹—OC(O)—R²⁰, —R²¹—N(R²⁰)₂,—R²¹—C(O)R²⁰, —R²¹—C(O)OR²⁰, —R²¹—C(O)N(R²⁰)₂, —R²¹—N(R²⁰)C(O)OR²⁰,—R²¹—N(R²⁰)C(O)R²⁰, —R²¹—N(R²⁰)S(O)₂R²⁰2, —R²¹—C(═NR²⁰)N(R²⁰)₂,—R²¹—S(O)_(t)OR²⁰ (where t is 1 or 2), —R²¹—S(O)_(p)R²⁰ (where p is 0, 1or 2), and —R²¹—S(O)₂N(R²⁰)₂, where each R²⁰ is independently selectedfrom the group consisting of hydrogen, alkyl, haloalkyl, optionallysubstituted cycloalkyl, optionally substituted cycloalkylalkyl,optionally substituted aryl, optionally substituted aralkyl, optionallysubstituted heterocyclyl, optionally substituted heterocyclylalkyl,optionally substituted heteroaryl and optionally substitutedheteroarylalkyl, or two R²⁰'s, together with the common nitrogen towhich they are both attached, form an optionally substitutedN-heterocyclyl or an optionally substituted N-heteroaryl, and each R²¹is independently a direct bond or a straight or branched alkylene oralkenylene chain.

“N-heteroaryl” refers to a heteroaryl radical as defined abovecontaining at least one nitrogen and where the point of attachment ofthe N-heteroaryl radical to the rest of the molecule may be through anitrogen atom in the N-heteroaryl radical or through a carbon atom inthe N-heteroaryl radical.

“Optionally substituted N-heteroaryl” refers to an N-heteroaryl, asdefined above, which is optionally substituted by one or moresubstituents as defined above for optionally substituted heteroaryl.

“Heteroarylalkyl” refers to a radical of the formula —R_(b)R_(i) whereR_(b) is an alkylene chain as defined above and R_(i) is a heteroarylradical as defined above, and when the heteroaryl is anitrogen-containing heteroaryl, the heteroaryl may be attached to thealkylene chain at the nitrogen atom.

“Optionally substituted heteroarylalkyl” refers to a heteroarylalkylradical, as defined above, wherein the alkylene chain of theheteroarylalkyl radical is an optionally substituted alkylene chain, asdefined above, and the heteroaryl radical of the heteroarylalkyl radicalis an optionally substituted heteroaryl radical, as defined above.

“Heteroarylalkenyl” refers to a radical of the formula —R_(d)R_(i) whereR_(d) is an alkenylene chain as defined above and R_(i) is a heteroarylradical as defined above, and when the heteroaryl is anitrogen-containing heteroaryl, the heteroaryl may be attached to thealkenylene chain at the nitrogen atom.

“Optionally substituted heteroarylalkenyl” refers to a heteroarylalkenylradical, as defined above, wherein the alkenylene chain of theheteroarylalkenyl radical is an optionally substituted alkenylene chain,as defined above, and the heteroaryl radical of the heteroarylalkenylradical is an optionally substituted heteroaryl radical, as definedabove.

“Heteroarylalkynyl” refers to a radical of the formula —R_(e)R_(i) whereR_(e) is an alkynylene chain as defined above and R_(i) is a heteroarylradical as defined above, and when the heteroaryl is anitrogen-containing heteroaryl, the heteroaryl may be attached to thealkynylene chain at the nitrogen atom.

“Optionally substituted heteroarylalkynyl” refers to a heteroarylalkynylradical, as defined above, wherein the alkynylene chain of theheteroarylalkynyl radical is an optionally substituted alkynylene chain,as defined above, and the heteroaryl radical of the heteroarylalkynylradical is an optionally substituted heteroaryl radical, as definedabove.

“Hydroxyalkyl” refers to an alkyl radical as defined above which issubstituted by one or more hydroxy radicals (—OH).

“Hydroxyalkenyl” refers to an alkenyl radical as defined above which issubstituted by one or more hydroxy radicals (—OH).

“Hydroxyalkenyl” refers to an alkynyl radical as defined above which issubstituted by one or more hydroxy radicals (—OH).

Certain chemical groups named herein may be preceded by a shorthandnotation indicating the total number of carbon atoms that are to befound in the indicated chemical group. For example; C₇-C₁₂alkyldescribes an alkyl group, as defined above, having a total of 7 to 12carbon atoms, and C₄-C₁₂cycloalkylalkyl describes a cycloalkylalkylgroup, as defined above, having a total of 4 to 12 carbon atoms. Thetotal number of carbons in the shorthand notation does not includecarbons that may exist in substituents of the group described.

“Stable compound” and “stable structure” are meant to indicate acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious therapeutic agent.

“Mammal” means any vertebrate of the class Mammalia. Humans and domesticanimals, such as cats, dogs, swine, cattle, sheep, goats, horses,rabbits, and the like are a particular focus. Frequently, for purposesof this invention, the mammal is a human.

“Optional” or “optionally” means that the subsequently described eventor circumstances may or may not occur, and that the description includesinstances where said event or circumstance occurs and instances in whichit does not. For example, “optionally substituted aryl” means that thearyl radical may or may not be substituted and that the descriptionincludes both substituted aryl radicals and aryl radicals having nosubstitution. However, when a first functional group is described as“optionally substituted,” and in turn, substituents on the firstfunctional group are also “optionally substituted” and so forth, for thepurposes of this invention, such iterations for a radical to beoptionally substituted are limited to three. Thus, groups described assubstituents on the third iteration are not themselves optionallysubstituted. For example, if an R group herein is defined as being“optionally substituted aryl” (the first iteration) and the optionalsubstituents for the “optionally substituted aryl” include “optionallysubstituted heteroaryl” (the second iteration) and the optionalsubstituents for the “optionally substituted heteroaryl” include“optionally substituted cycloalkyl” (the third iteration), the optionalsubstituents on the cycloalkyl can not be optionally substituted.

“Para” for the purposes of this invention refers to the position of asubstituent on a phenyl or a six-membered heteroaryl ring relative toanother substituent on the ring; the relative position being1,4-substitution. That is, starting from one substituent as beingattached to a first atom of the phenyl or six-membered heteroaryl ringand, counting atoms in the ring from the first atom, another substituentis on atom 4 of the phenyl or the six-membered heteroaryl ring, thesubstituents' relative orientation about the phenyl or six-memberedheteroaryl ring is “para.” For example, a compound of formula (I), asset forth above in the Summary of the Invention, depicted below as acompound of formula (Ia-1), where R⁵ is on a first atom of the phenylring, and the nitrogen bearing R¹ is on the fourth atom, then R⁵ and thenitrogen bearing R¹ are “para” in relative orientation.

“Meta” for the purposes of this invention refers to the position of asubstituent on a phenyl or a six-membered heteroaryl ring relative toanother substituent on the ring; the relative position being1,3-substitution. That is, starting from one substituent as beingattached to a first atom of the phenyl or six-membered heteroaryl ringand, counting atoms in the ring from the first atom, another substituentis on the third atom of the phenyl or the six-membered heteroaryl ring,the substituents' relative orientation about the phenyl or thesix-membered heteroaryl ring is “meta.” For example, a compound offormula (I), as set forth above in the Summary of the Invention,depicted below as a compound of formula (Ia-1c), where R² is on a firstatom of the phenyl ring, and the nitrogen bearing hydrogen is on a thirdatom, then R² and the nitrogen bearing hydrogen are “para” in relativeorientation.

“Pharmaceutically acceptable excipient” includes without limitation anyadjuvant, carrier, excipient, glidant, sweetening agent, diluent,preservative, dye/colorant, flavor enhancer, surfactant, wetting agent,dispersing agent, suspending agent, stabilizer, isotonic agent, solvent,or emulsifier which has been approved by the United States Food and DrugAdministration as being acceptable for use in humans or domesticanimals.

“Pharmaceutically acceptable salt” includes both acid and base additionsalts.

“Pharmaceutically acceptable acid addition salt” refers to those saltswhich retain the biological effectiveness and properties of the freebases, which are not biologically or otherwise undesirable, and whichare formed with inorganic acids such as, but not limited to,hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid and the like, and organic acids such as, but not limitedto, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid,ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid,4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid,capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid,citric acid, cyclamic acid, dodecylsulfonic acid, ethane-1,2-disulfonicacid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid,fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid,gluconic acid, glucuronic acid, glutamic acid, glutaric acid,2-oxo-glutaric acid, glycerophosphoric acid, glycolic acid, hippuricacid, isobutyric acid, lactic acid, lactobionic acid, lauric acid,maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonicacid, mucic acid, naphthalene-1,5-disulfonic acid,naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid,oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid,propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid,4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid,tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroaceticacid, undecylenic acid, and the like.

“Pharmaceutically acceptable base addition salt” refers to those saltswhich retain the biological effectiveness and properties of the freeacids, which are not biologically or otherwise undesirable. These saltsare prepared from addition of an inorganic base or an organic base tothe free acid. Salts derived from inorganic bases include, but are notlimited to, the sodium, potassium, lithium, ammonium, calcium,magnesium, iron, zinc, copper, manganese, aluminum salts and the like.Preferred inorganic salts are the ammonium, sodium, potassium, calcium,and magnesium salts. Salts derived from organic bases include, but arenot limited to, salts of primary, secondary, and tertiary amines,substituted amines including naturally occurring substituted amines,cyclic amines and basic ion exchange resins, such as ammonia,isopropylamine, trimethylamine, diethylamine, triethylamine,tripropylamine, diethanolamine, ethanolamine, 2-dimethylaminoethanol,2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine,caffeine, procaine, hydrabamine, choline, betaine, benethamine,benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine,triethanolamine, tromethamine, purines, piperazine, piperidine,N-ethylpiperidine, polyamine resins and the like. Particularly preferredorganic bases are isopropylamine, diethylamine, ethanolamine,trimethylamine, dicyclohexylamine, choline and caffeine.

A “pharmaceutical composition” refers to a formulation of a compound ofthe invention and a medium generally accepted in the art for thedelivery of the biologically active compound to mammals, for example,humans. Such a medium includes all pharmaceutically acceptable carriers,diluents or excipients therefor.

“Therapeutically effective amount” refers to that amount of a compoundof the invention which, when administered to a mammal, for example ahuman, is sufficient to effect treatment, as defined below, of a diseaseor condition of interest in the mammal, preferably a human. The amountof a compound of the invention which constitutes a “therapeuticallyeffective amount” will vary depending on the compound, the disease orcondition and its severity, and the age of the mammal to be treated, butcan be determined routinely by one of ordinary skill in the art havingregard to his own knowledge and to this disclosure.

“Treating” or “treatment” as used herein covers the treatment of thedisease or condition of interest in a mammal, for example a human,having the disease or condition of interest, and includes:

(i) preventing the disease or condition or one of its manifestations orsymptoms from occurring in a mammal, in particular, when such mammal ispredisposed to the condition but has not yet been diagnosed as havingit;

(ii) inhibiting the disease or condition, i.e., arresting itsdevelopment or one or more of its manifestations or symptoms;

(iii) relieving the disease or condition, i.e., causing regression ofthe disease or condition or one if its manifestations or symptoms; or

(iv) stabilizing the disease or condition or one of its manifestationsor symptoms.

As used herein, the terms “disease” and “condition” may be usedinterchangeably or may be different in that the particular malady orcondition may not have a known causative agent (so that etiology has notyet been worked out) and it is therefore not yet recognized as a diseasebut only as an undesirable condition or syndrome, wherein a more or lessspecific set of symptoms have been identified by clinicians.

The compounds of the invention, or their pharmaceutically acceptablesalts may contain one or more asymmetric centres and may thus give riseto enantiomers, diastereomers, and other stereoisomeric forms that maybe defined, in terms of absolute stereochemistry, as (R)- or (S)- or, as(D)- or (L)- for amino acids. The present invention is meant to includeall such possible isomers, as well as their racemic and optically pureforms. Likewise, all tautomeric forms of the specifically describedstructures are also intended to be included. Optically active (+) and(−), (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiralsynthons or chiral reagents, or resolved using conventional techniques,such as HPLC using a chiral column. When the compounds described hereincontain olefinic double bonds or other centres of geometric asymmetry,and unless specified otherwise, it is intended that the compoundsinclude both E and Z geometric isomers. Similarly, with reference tobicyclic ring systems present in particular embodiments, such moietiesoften may have substituents attached in an “endo” or “exo” relativeconfiguration. The stereochemical descriptor “endo” refers to a bridgesubstituent that points toward the larger of the two remaining bridges.If the substituent points toward the smaller remaining bridge, it isreferred to as an “exo” substituent.

When used herein in a formula to indicate a chemical bond and not toindicate the point of attachment of a substituent to the rest of amolecule (as shown in Tables 2 and 3 below), the bond symbol

indicates that the chemical bond may be attached in any relative orabsolute configuration, for example, the chemical bond may be in an endoor exo relative configuration. Similarly, the chemical bond may beattached in the R or S absolute configuration.

A “stereoisomer” refers to a compound made up of the same atoms bondedby the same bonds but having different three-dimensional structures,which are not interchangeable. The present invention contemplatesvarious stereoisomers and mixtures thereof and includes “enantiomers”,which refers to two stereoisomers whose molecules are nonsuperimposeablemirror images of one another.

A “tautomer” refers to a proton shift from one atom of a molecule toanother atom of the same molecule. The present invention includestautomers of any said compounds.

“Atropisomers” are stereoisomers resulting from hindered rotation aboutsingle bonds where the barrier to rotation is high enough to allow forthe isolation of the conformers (Eliel, E. L.; Wilen, S. H.Stereochemistry of Organic Compounds; Wiley & Sons: New York, 1994;Chapter 14). Atropisomerism is significant because it introduces anelement of chirality in the absence of stereogenic atoms. The inventionis meant to encompass atropisomers, for example in cases of limitedrotation around the single bonds emanating from the core pyrimidinestructure, atropisomers are also possible and are also specificallyincluded in the compounds of the invention.

The chemical naming protocol and structure diagrams used herein are amodified form of the I.U.P.A.C. nomenclature system wherein thecompounds of the invention are named herein as derivatives of thecentral core structure, i.e., the pyrimidine-2-amine structure. Forcomplex chemical names employed herein, a substituent group is namedbefore the group to which it attaches. For example, cyclopropylethylcomprises an ethyl backbone with cyclopropyl substituent. In chemicalstructure diagrams, all bonds are identified, except for some carbonatoms which are assumed to be bonded to sufficient hydrogen atoms tocomplete the valency.

For example, a compound of formula (I), as set forth above in theSummary of the Invention, wherein n is 0, m is 1,

is phenyl, R¹ is hydrogen, R² is fluoro at the meta position, R⁴ is6-(4-acetylpiperazin-1-yl)pyridin-3-yl and R⁵ is(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl at the para positionrelative to the nitrogen bearing hydrogen, i.e., a compound of thefollowing formula (wherein the positions of the pyrimidinyl ring areindicated):

is named herein as4-(6-(4-acetylpiperazin-1-yl)pyridin-3-yl)-N-(3-fluoro-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine.

EMBODIMENTS OF THE INVENTION

One aspect of the invention are compounds of formula (I), as set forthabove in the Summary of the Invention, as an isolated stereoisomer or amixture thereof, or as a pharmaceutically acceptable salt thereof. Ofthis aspect, certain embodiments of the compounds of formula (I) arepreferred.

In one embodiment, ring A in the compounds of formula (I) is a phenyl orpyridinyl ring. Of this embodiment, one embodiment is wherein R⁵ is abridged N-heterocyclyl. Of this embodiment, a preferred embodiment iswherein the bridged N-heterocyclyl is selected from the group consistingof:

where each R^(5a) is independently selected from the group consisting ofhydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl,optionally substituted aryl, optionally substituted aralkyl, optionallysubstituted aralkenyl, optionally substituted aralkynyl, optionallysubstituted cycloalkyl, optionally substituted cycloalkylalkyl,optionally substituted cycloalkylalkenyl, optionally substitutedcycloalkylalkynyl, optionally substituted heterocyclyl, optionallysubstituted heterocyclylalkyl, optionally substitutedheterocyclylalkenyl, optionally substituted heterocyclylalkynyl,optionally substituted heteroaryl, optionally substitutedheteroarylalkyl, optionally substituted heteroarylalkenyl, optionallysubstituted heteroarylalkynyl, —R⁸—OR⁶, —R⁸—C(O)R⁶, —R⁸—C(O)OR⁶,—R⁹—N(R⁶)R⁷, —R⁸—C(O)N(R⁶)R⁷, —R⁸—C(N═R⁶)N(R⁶)R⁷, —R⁸—S(O)₂N(R⁶)R⁷, and—R⁸—S(O)_(t)R⁶ where t is 1 or 2 and each R⁶, R⁷, R⁸ and R⁹ is asdefined above in the Summary of the Invention for compounds of formula(I), and where each R²⁰ is independently selected from the groupconsisting of hydrogen, alkyl, haloalkyl, optionally substitutedcycloalkyl, optionally substituted cycloalkylalkyl, optionallysubstituted aryl, optionally substituted aralkyl, optionally substitutedheterocyclyl, optionally substituted heterocyclylalkyl, optionallysubstituted heteroaryl and optionally substituted heteroarylalkyl, ortwo R²⁰'s, together with the common nitrogen to which they are bothattached, form an optionally substituted N-heterocyclyl or an optionallysubstituted N-heteroaryl.

Another embodiment of the compounds of formula (I), as set forth abovein the Summary of the Invention, are compounds wherein R⁵ is a bridgedN-heterocyclyl, or wherein a R⁴ substituent is a bridged N-heterocyclyl,or wherein R⁵ and a R⁴ substitutent are both bridged N-heterocycyls. Incertain embodiments of this invention, R⁵ is a bridged N-heterocyclyl.

In the compounds of formula (I) wherein R⁵ is a bridged N-heterocyclylor the R⁴ substituent is a N-heterocyclyl, R⁵ and the R⁴ substituentneed not be attached to ring A or R⁴, respectively, via a ring nitrogenof the bridged N-heterocyclyl, but rather can be attached via a ringcarbon, for example. In some embodiments, a bridged N-heterocyclyl as R⁵or as a R⁴ substituent is fused to another ring, part of a spiro ringsystem or both. In certain embodiments, a bridged N-heterocyclyl as R⁵or as a R⁴ substituent, alone or as part of a larger fused, spiro orcombination ring system, comprises a substructure geometry selected fromthe group consisting of [4.4.0], [4.3.0], [4.2.0], [4.1.0], [3.3.0],[3.2.0], [3.1.0], [3.3.3], [3.3.2], [3.3.1], [3.2.2], [3.2.1], [2.2.2]and [2.2.1].

In one embodiment, the bridged N-heterocyclyl as R⁵ or as an R⁴substituent, independently if more than one, is selected from the groupconsisting of:

where each R^(5a) is independently selected from the group consisting ofhydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl,optionally substituted aryl, optionally substituted aralkyl, optionallysubstituted aralkenyl, optionally substituted aralkynyl, optionallysubstituted cycloalkyl, optionally substituted cycloalkylalkyl,optionally substituted cycloalkylalkenyl, optionally substitutedcycloalkylalkynyl, optionally substituted heterocyclyl, optionallysubstituted heterocyclylalkyl, optionally substitutedheterocyclylalkenyl, optionally substituted heterocyclylalkynyl,optionally substituted heteroaryl, optionally substitutedheteroarylalkyl, optionally substituted heteroarylalkenyl, optionallysubstituted heteroarylalkynyl, —R⁸—OR⁶, —R⁸—C(O)R⁶, —R⁸—C(O)OR⁶,—R⁹—N(R⁶)R⁷, —R⁸—C(O)N(R⁶)R⁷, —R⁸—C(N═R⁶)N(R⁶)R⁷, —R⁸—S(O)₂N(R⁶)R⁷, and—R⁸—S(O)_(t)R⁶ where t is 1 or 2 and each R⁶, R⁷, R⁸ and R⁹ is asdefined above in the Summary of the Invention for compounds of formula(I) and where each R²⁰ is independently selected from the groupconsisting of hydrogen, alkyl, haloalkyl, optionally substitutedcycloalkyl, optionally substituted cycloalkylalkyl, optionallysubstituted aryl, optionally substituted aralkyl, optionally substitutedheterocyclyl, optionally substituted heterocyclylalkyl, optionallysubstituted heteroaryl and optionally substituted heteroarylalkyl, ortwo R²⁰'s, together with the common nitrogen to which they are bothattached, form an optionally substituted N-heterocyclyl or an optionallysubstituted N-heteroaryl.

In a particular embodiment, R⁵ is a bridged N-heterocyclyl and R⁴ is aheteroaryl optionally substituted with a bridged N-heterocyclyl. Inexemplary compounds of the invention for this embodiment, R⁵ is abridged N-heterocyclyl containing an additional nitrogen, R⁴ is a 5- or6-membered heteroaryl and n is 0. In a specific embodiment, R⁵ and thenitrogen bearing R¹ are in a para regiochemical relationship with eachother and R⁴ is selected from pyridyl, pyridazinyl, pyrimidinyl,pyrazinyl, triazinyl triazolyl, tetrazinyl, tetrazolyl, pyrazolyl,pyrrolyl, imidazolyl and pyrazolyl. In certain embodiments, R⁴ issubstituted with an amino-containing group, e.g., —R⁸—N(R^(6a))R^(7a),—R⁸—N(R^(6a))—R⁹—N(R^(6a))R^(7a) or —R⁸—N(R^(6a))—R⁹—OR^(7a), where eachR^(6a), R^(7a), R⁸ and R⁹ are as described above in the Summary of theInvention for compounds of formula (I), or R⁴ is substituted with anoptionally substituted heterocyclyl, e.g. an optionally substitutedpiperidinyl, optionally substituted piperazinyl, optionally substitutedmorpholinyl, and optionally substituted thiomorpholinyl. In someexamples of this embodiment, R⁴ is substituted with a bridgedN-heterocyclyl. In further examples, ring A and/or R⁴ are substitutedwith up to three additional substituents selected from the groupconsisting of halo, alkyl, haloalkyl, cyano, nitro, hydroxy, —OR²⁵,—N(R²⁵)₂, —C(O)OR²⁵, —C(O)N(R²⁵)₂ and combinations thereof; where eachR²⁵ is independently selected from the group consisting of hydrogen,alkyl, haloalkyl, cycloalkyl and cycloalkylalkyl.

Another embodiment of the invention is a compound of formula (I), as setforth above in the Summary of the Invention, according to formula (Ia):

wherein:

-   n is 0, 1 or 2;-   m is 0, 1 or 2;-   Y is selected from the group consisting of ═C(R⁶)— and ═N—;-   R¹ is selected from the group consisting of hydrogen, alkyl,    alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkenyl, optionally    substituted cycloalkyl, optionally substituted cycloalkylalkyl,    optionally substituted cycloalkylalkenyl, optionally substituted    cycloalkylalkynyl, optionally substituted aryl, optionally    substituted aralkyl, optionally substituted aralkenyl, optionally    substituted aralkynyl, —R⁸—C(O)OR⁶, —R⁹—N(R⁶)R⁷ and —R⁹—OR⁶;-   each R², when present, is independently selected from the group    consisting of optionally substituted alkyl, halo, cyano and —OR⁶;-   each R³, when present, is independently selected from the group    consisting of alkyl, halo and haloalkyl;-   R⁴ is selected from the group consisting of aryl and heteroaryl,    where the aryl and the heteroaryl are each independently optionally    substituted by one or more substituents selected from the group    consisting of oxo, alkyl, halo, haloalkyl, cyano, N-heterocyclyl,    N-heteroaryl, aryl, —R⁸—OR^(6a), —R⁸—S(O)_(p)R^(6a) (where p is 0, 1    or 2), —R⁸—C(O)R^(6a), —R⁸—C(O)OR^(6a), —R⁸—C(O)N(R^(6a))R^(7a),    —R⁸—N(R^(6a))R^(7a), —R⁸—N(R^(6a))—R⁹—N(R^(6a))R^(7a),    —R⁸—N(R^(6a))—R⁹—OR^(7a), —R⁸—N(R^(6a))C(O)R^(7a),    —R⁸—N(R^(6a))S(O)₂R^(7a), —R⁸—N(R^(6a))C(O)—R⁸—N(R^(6a))R^(7a), and    —R⁸—N(R^(6a))—R⁹—N(R^(6a))S(O)₂R^(7a), where each R^(6a) and R^(7a)    is independently selected from the group consisting of hydrogen,    alkyl, optionally substituted cycloalkyl, optionally substituted    heterocyclyl, optionally substituted heterocyclylalkyl, optionally    substituted heteroaryl and optionally substituted aralkyl, and where    the N-heterocyclyl, the N-heteroaryl and the aryl are each    independently optionally substituted by one or more substituents    selected from the group consisting of —C(O)R⁶, —R⁸—N(R⁶)R⁷,    —R⁸—C(O)N(R⁶)R⁷, alkyl, halo and optionally substituted aryl, and    when any R^(6a) and R^(7a) are bonded to a common nitrogen, R^(6a)    and R^(7a) together with the common nitrogen to which they are both    attached, may form an optionally substituted N-heteroaryl or an    optionally substituted N-heterocyclyl;-   R⁵ is an N-heterocyclyl, wherein a nitrogen atom in the    N-heterocyclyl is optionally substituted by a substituent selected    from the group consisting of alkyl, alkenyl, alkynyl, haloalkyl,    haloalkenyl, haloalkynyl, optionally substituted aryl, optionally    substituted aralkyl, optionally substituted aralkenyl, optionally    substituted aralkynyl, optionally substituted cycloalkyl, optionally    substituted cycloalkylalkyl, optionally substituted    cycloalkylalkenyl, optionally substituted cycloalkylalkynyl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, optionally substituted heterocyclylalkenyl,    optionally substituted heterocyclylalkynyl, optionally substituted    heteroaryl, optionally substituted heteroarylalkyl, optionally    substituted heteroarylalkenyl, optionally substituted    heteroarylalkynyl, —R⁸—OR⁶, —R⁸—C(O)R⁶, —R⁸—C(O)OR⁶, —R⁹—N(R⁶)R⁷,    —R⁸—C(O)N(R⁶)R⁷, —R⁸—C(N═R⁶)N(R⁶)R⁷, —R⁸—S(O)₂N(R⁶)R⁷, and    —R⁸—S(O)_(t)R⁶ (where t is 1 or 2); and a carbon atom in the    N-heterocyclyl is optionally substituted by a substituent selected    from the group consisting of alkyl, alkenyl, alkynyl, halo,    haloalkyl, haloalkenyl, haloalkynyl, oxo, optionally substituted    aryl, optionally substituted aralkyl, optionally substituted    aralkenyl, optionally substituted aralkynyl, optionally substituted    cycloalkyl, optionally substituted cycloalkylalkyl, optionally    substituted cycloalkylalkenyl, optionally substituted    cycloalkylalkynyl, optionally substituted heterocyclyl, optionally    substituted heterocyclylalkyl, optionally substituted    heterocyclylalkenyl, optionally substituted heterocyclylalkynyl,    optionally substituted heteroaryl, optionally substituted    heteroarylalkyl, optionally substituted heteroarylalkenyl,    optionally substituted heteroarylalkynyl, —R⁸—OR⁶, —R⁸—C(O)R⁶,    —R⁸—C(O)OR⁶, —R⁹—N(R⁶)R⁷, —R⁸—C(O)N(R⁶)R⁷, —R⁸—S(O)₂N(R⁶)R⁷, and    —R⁸—S(O)_(p)R⁶ (where p is 0, 1 or 2);-   each R⁶ and each R⁷ is independently selected from the group    consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl,    haloalkenyl, haloalkynyl, optionally substituted cycloalkyl,    optionally substituted cycloalkylalkyl, optionally substituted aryl,    optionally substituted aralkyl, optionally substituted aralkenyl,    optionally substituted aralkynyl, optionally substituted    heterocyclyl, optionally substituted heterocyclylalkyl, optionally    substituted heterocyclylalkenyl, optionally substituted    heterocyclylalkynyl, optionally substituted heteroaryl, optionally    substituted heteroarylalkyl, optionally substituted    heteroarylalkenyl, and optionally substituted heteroarylalkynyl; or    any R⁶ and R⁷, together with the common nitrogen to which they are    both attached, form an optionally substituted N-heteroaryl or an    optionally substituted N-heterocyclyl;-   each R⁸ is independently selected from the group consisting of a    direct bond, an optionally substituted straight or branched alkylene    chain, an optionally substituted straight or branched alkenylene    chain and an optionally substituted straight or branched alkynylene    chain; and-   each R⁹ is independently selected from the group consisting of an    optionally substituted straight or branched alkylene chain, an    optionally substituted straight or branched alkenylene chain and an    optionally substituted straight or branched alkynylene chain;-   provided at least one of R⁵ and a substituent on R⁴ is a bridged    N-heterocyclyl;    as an isolated stereoisomer or a mixture thereof, or as a    pharmaceutically acceptable salt thereof.

One embodiment of the compounds of formula (Ia) is a compound of formula(Ia), as set forth above, wherein:

m is 0 or 1;

R², when present, is in a meta position relative to the nitrogen bearingR¹; and

R⁵ is in the para position relative to the nitrogen bearing R¹.

One embodiment of the compounds of formula (Ia) is a compound of formula(Ia), as set forth above, wherein:

n is 0 or 1; and

R³, when present, is at the 5-position of the pyrimidinyl ring.

One embodiment of the compounds of formula (Ia) is a compound of formula(Ia), as set forth above, wherein:

m is 0 or 1;

n is 0 or 1;

R², when present, is in a meta position relative to the nitrogen bearingR¹;

R³, when present, is at the 5-position of the pyrimidinyl ring; and

R⁵ is in the para position relative to the nitrogen bearing R¹.

One embodiment of the invention is a compound of formula (I), as setforth above in the Summary of the Invention, according to formula(Ia-1):

wherein:

-   n is 0, 1 or 2;-   m is 0, 1 or 2;-   R¹ is selected from the group consisting of hydrogen, alkyl,    alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkenyl, optionally    substituted cycloalkyl, optionally substituted cycloalkylalkyl,    optionally substituted cycloalkylalkenyl, optionally substituted    cycloalkylalkynyl, optionally substituted aryl, optionally    substituted aralkyl, optionally substituted aralkenyl, optionally    substituted aralkynyl, —R⁸—C(O)OR⁶, —R⁹—N(R⁶)R⁷ and —R⁹—OR⁶;-   each R², when present, is independently selected from the group    consisting of optionally substituted alkyl, halo, cyano and —OR⁶;-   each R³, when present, is independently selected from the group    consisting of alkyl, halo and haloalkyl;-   R⁴ is selected from the group consisting of aryl and heteroaryl,    where the aryl and the heteroaryl are each independently optionally    substituted by one or more substituents selected from the group    consisting of oxo, alkyl, halo, haloalkyl, cyano, N-heterocyclyl,    N-heteroaryl, aryl, —R⁸—OR^(6a), —R⁸—S(O)_(p)R^(6a) (where p is 0, 1    or 2), —R⁸—C(O)R^(6a), —R⁸—C(O)OR^(6a), —R⁸—C(O)N(R^(6a))R^(7a),    —R⁸—N(R^(6a))R^(7a), —R⁸—N(R^(6a))—R⁹—N(R^(6a))R^(7a),    —R⁸—N(R^(6a))—R⁹—OR^(7a), —R⁸—N(R^(6a))C(O)R^(7a),    —R⁸—N(R^(6a))S(O)₂R^(7a), —R⁸—N(R^(6a))C(O)—R⁸—N(R^(6a))R^(7a), and    —R⁸—N(R^(6a))—R⁹—N(R^(6a))S(O)₂R^(7a), where each R^(6a) and R^(7a)    is independently selected from the group consisting of hydrogen,    alkyl, optionally substituted cycloalkyl, optionally substituted    heterocyclyl, optionally substituted heterocyclylalkyl, optionally    substituted heteroaryl and optionally substituted aralkyl, and where    the N-heterocyclyl, the N-heteroaryl and the aryl are each    independently optionally substituted by one or more substituents    selected from the group consisting of —C(O)R⁶, —R⁸—N(R⁶)R⁷,    —R⁸—C(O)N(R⁶)R⁷, alkyl, halo and optionally substituted aryl, and    when any R^(6a) and R^(7a) are bonded to a common nitrogen, R^(6a)    and R^(7a) together with the common nitrogen to which they are both    attached, may form an optionally substituted N-heteroaryl or an    optionally substituted N-heterocyclyl;-   R⁵ is an N-heterocyclyl, wherein a nitrogen atom in the    N-heterocyclyl is optionally substituted by a substituent selected    from the group consisting of alkyl, alkenyl, alkynyl, haloalkyl,    haloalkenyl, haloalkynyl, optionally substituted aryl, optionally    substituted aralkyl, optionally substituted aralkenyl, optionally    substituted aralkynyl, optionally substituted cycloalkyl, optionally    substituted cycloalkylalkyl, optionally substituted    cycloalkylalkenyl, optionally substituted cycloalkylalkynyl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, optionally substituted heterocyclylalkenyl,    optionally substituted heterocyclylalkynyl, optionally substituted    heteroaryl, optionally substituted heteroarylalkyl, optionally    substituted heteroarylalkenyl, optionally substituted    heteroarylalkynyl, —R⁸—OR⁶, —R⁸—C(O)R⁶, —R⁸—C(O)OR⁶, —R⁹—N(R⁶)R⁷,    —R⁸—C(O)N(R⁶)R⁷, —R⁸—C(N═R⁶)N(R⁶)R⁷, —R⁸—S(O)₂N(R⁶)R⁷, and    —R⁸—S(O)_(t)R⁶ (where t is 1 or 2); and a carbon atom in the    N-heterocyclyl is optionally substituted by a substituent selected    from the group consisting of alkyl, alkenyl, alkynyl, halo,    haloalkyl, haloalkenyl, haloalkynyl, oxo, optionally substituted    aryl, optionally substituted aralkyl, optionally substituted    aralkenyl, optionally substituted aralkynyl, optionally substituted    cycloalkyl, optionally substituted cycloalkylalkyl, optionally    substituted cycloalkylalkenyl, optionally substituted    cycloalkylalkynyl, optionally substituted heterocyclyl, optionally    substituted heterocyclylalkyl, optionally substituted    heterocyclylalkenyl, optionally substituted heterocyclylalkynyl,    optionally substituted heteroaryl, optionally substituted    heteroarylalkyl, optionally substituted heteroarylalkenyl,    optionally substituted heteroarylalkynyl, —R⁸—OR⁶, —R⁸—C(O)R⁶,    —R⁸—C(O)OR⁶, —R⁹—N(R⁶)R⁷, —R⁸—C(O)N(R⁶)R⁷, —R⁸—S(O)₂N(R⁶)R⁷, and    —R⁸—S(O)_(p)R⁶ (where p is 0, 1 or 2);-   each R⁶ and each R⁷ is independently selected from the group    consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl,    haloalkenyl, haloalkynyl, optionally substituted cycloalkyl,    optionally substituted cycloalkylalkyl, optionally substituted aryl,    optionally substituted aralkyl, optionally substituted aralkenyl,    optionally substituted aralkynyl, optionally substituted    heterocyclyl, optionally substituted heterocyclylalkyl, optionally    substituted heterocyclylalkenyl, optionally substituted    heterocyclylalkynyl, optionally substituted heteroaryl, optionally    substituted heteroarylalkyl, optionally substituted    heteroarylalkenyl, and optionally substituted heteroarylalkynyl; or    any R⁶ and R⁷, together with the common nitrogen to which they are    both attached, form an optionally substituted N-heteroaryl or an    optionally substituted N-heterocyclyl;-   each R⁸ is independently selected from the group consisting of a    direct bond, an optionally substituted straight or branched alkylene    chain, an optionally substituted straight or branched alkenylene    chain and an optionally substituted straight or branched alkynylene    chain; and-   each R⁹ is independently selected from the group consisting of an    optionally substituted straight or branched alkylene chain, an    optionally substituted straight or branched alkenylene chain and an    optionally substituted straight or branched alkynylene chain;-   provided at least one of R⁵ and a substituent on R⁴ is a bridged    N-heterocyclyl.

Of the compounds of formula (Ia-1), as set forth above, one embodimentis a compound selected from the following formulae:

wherein:

-   each n is 0, 1 or 2;-   each R²² is independently selected from the group consisting of    hydrogen, optionally substituted alkyl, halo, cyano and —OR⁶;-   each R³, when present, is independently selected from the group    consisting of alkyl, halo and haloalkyl;-   each R⁴ is independently selected from the group consisting of aryl    and heteroaryl, where the aryl and the heteroaryl are each    independently optionally substituted by one or more substituents    selected from the group consisting of oxo, alkyl, halo, haloalkyl,    cyano, N-heterocyclyl, N-heteroaryl, aryl, —R⁸—OR^(6a),    —R⁸—S(O)_(p)R^(6a) (where p is 0, 1 or 2), —R⁸—C(O)R^(6a),    —R⁸—C(O)OR^(6a), —R⁸—C(O)N(R^(6a))R^(7a), —R⁸—N(R^(6a))R^(7a),    —R⁸—N(R^(6a))—R⁹—N(R^(6a))R^(7a), —R⁸—N(R^(6a))—R⁹—OR^(7a),    —R⁸—N(R^(6a))C(O)R^(7a), —R⁸—N(R^(6a))S(O)₂R^(7a),    —R⁸—N(R^(6a))C(O)—R⁸—N(R^(6a))R^(7a), and    —R⁸—N(R^(6a))—R⁹—N(R^(6a))S(O)₂R^(7a), where each R^(6a) and R^(7a)    is independently selected from the group consisting of hydrogen,    alkyl, optionally substituted cycloalkyl, optionally substituted    heterocyclyl, optionally substituted heterocyclylalkyl, optionally    substituted heteroaryl and optionally substituted aralkyl, and where    the N-heterocyclyl, the N-heteroaryl and the aryl are each    independently optionally substituted by one or more substituents    selected from the group consisting of —C(O)R⁶, —R⁸—N(R⁶)R⁷,    —R⁸—C(O)N(R⁶)R⁷, alkyl, halo and optionally substituted aryl, and    when any R^(6a) and R^(7a) are bonded to a common nitrogen, R_(6a)    and R^(7a) together with the common nitrogen to which they are both    attached, may form an optionally substituted N-heteroaryl or an    optionally substituted N-heterocyclyl;-   each R^(5a) is independently selected from the group consisting of    hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl,    haloalkynyl, optionally substituted aryl, optionally substituted    aralkyl, optionally substituted aralkenyl, optionally substituted    aralkynyl, optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted cycloalkylalkenyl,    optionally substituted cycloalkylalkynyl, optionally substituted    heterocyclyl, optionally substituted heterocyclylalkyl, optionally    substituted heterocyclylalkenyl, optionally substituted    heterocyclylalkynyl, optionally substituted heteroaryl, optionally    substituted heteroarylalkyl, optionally substituted    heteroarylalkenyl, optionally substituted heteroarylalkynyl,    —R⁸—OR⁶, —R⁸—C(O)R⁶, —R⁸—C(O)OR⁶, —R⁹—N(R⁶)R⁷, —R⁸—C(O)N(R⁶)R⁷,    —R⁸—C(N═R⁶)N(R⁶)R⁷, —R⁸—S(O)₂N(R⁶)R⁷, and —R⁸—S(O)_(t)R⁶ (where t is    1 or 2);-   each R⁶ and each R⁷ is independently selected from the group    consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl,    haloalkenyl, haloalkynyl, optionally substituted cycloalkyl,    optionally substituted cycloalkylalkyl, optionally substituted aryl,    optionally substituted aralkyl, optionally substituted aralkenyl,    optionally substituted aralkynyl, optionally substituted    heterocyclyl, optionally substituted heterocyclylalkyl, optionally    substituted heterocyclylalkenyl, optionally substituted    heterocyclylalkynyl, optionally substituted heteroaryl, optionally    substituted heteroarylalkyl, optionally substituted    heteroarylalkenyl, and optionally substituted heteroarylalkynyl; or    any R⁶ and R⁷, together with the common nitrogen to which they are    both attached, form an optionally substituted N-heteroaryl or an    optionally substituted N-heterocyclyl;-   each R⁸ is independently selected from the group consisting of a    direct bond, an optionally substituted straight or branched alkylene    chain, an optionally substituted straight or branched alkenylene    chain and an optionally substituted straight or branched alkynylene    chain; and-   each R⁹ is independently selected from the group consisting of an    optionally substituted straight or branched alkylene chain, an    optionally substituted straight or branched alkenylene chain and an    optionally substituted straight or branched alkynylene chain.

Of this embodiment, one embodiment is a compound selected from theformulae above wherein:

-   each n is 0 or 1;-   each R⁴ is independently selected from the group consisting of    phenyl, benzimidazolyl, benzo[b][1,4]oxazinyl, benzo[b]azepinyl,    2,3,4,5-tetrahydro-1H-benzo[b]azepinyl,    3,4-dihydro-2H-benzo[b][1,4]thiazinyl,    3′,4′-dihydrospiro[cyclobutane-1,2′-pyrido[3,2-b][1,4]oxazinyl,    3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl,    3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazinyl, imidazo[1,2-a]pyridinyl,    6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indolyl,    7,8,9,9a-tetrahydro-5H-pyrido[2,3-e]pyrrolo[1,2-a][1,4]diazepin-10(11H)-onyl,    indolyl, indolinyl, naphthyridinyl, pyrazolyl, pyridinyl, pyrazinyl,    pyrimidinyl, pyrrolyl, 1H-pyrrolo[2,3-b]pyridinyl, and thiazolyl,    each optionally substituted by one or more substituents    independently selected from the group consisting of oxo, alkyl,    halo, haloalkyl, cyano, N-heterocyclyl, N-heteroaryl, aryl,    —R⁸—OR^(6a), —R⁸—S(O)_(p)R^(6a) (where p is 0, 1 or 2),    —R⁸—C(O)R^(6a), —R⁸—C(O)OR^(6a), —R⁸—C(O)N(R^(6a))R^(7a),    —R⁸—N(R^(6a))R^(7a), —R⁸—N(R^(6a))—R⁹—N(R^(6a))R^(7a),    —R⁸—N(R^(6a))—R⁹—OR^(7a), —R⁸—N(R^(6a))C(O)R^(7a),    —R⁸—N(R^(6a))S(O)₂R^(7a), —R⁸—N(R^(6a))C(O)—R⁸—N(R^(6a))R^(7a), and    —R⁸—N(R^(6a))—R⁹—N(R^(6a))S(O)₂R^(7a), where the N-heterocyclyl, the    N-heteroaryl and the aryl are each independently optionally    substituted by one or more substituents selected from the group    consisting of —C(O)R⁶, —R⁸—N(R⁶)R⁷, —R⁸—C(O)N(R⁶)R⁷, alkyl, halo and    optionally substituted aryl;-   each R⁶ and each R⁷ is independently selected from the group    consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl,    haloalkenyl, haloalkynyl, optionally substituted cycloalkyl,    optionally substituted cycloalkylalkyl, optionally substituted aryl,    optionally substituted aralkyl, optionally substituted aralkenyl,    optionally substituted aralkynyl, optionally substituted    heterocyclyl, optionally substituted heterocyclylalkyl, optionally    substituted heterocyclylalkenyl, optionally substituted    heterocyclylalkynyl, optionally substituted heteroaryl, optionally    substituted heteroarylalkyl, optionally substituted    heteroarylalkenyl, and optionally substituted heteroarylalkynyl; or    any R⁶ and R⁷, together with the common nitrogen to which they are    both attached, form an optionally substituted N-heteroaryl or an    optionally substituted N-heterocyclyl;-   R^(6a) and R^(7a) are each independently selected from the group    consisting of hydrogen, alkyl, optionally substituted cycloalkyl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, optionally substituted heteroaryl, and optionally    substituted aralkyl, and when any R^(6a) and R^(7a) are bonded to a    common nitrogen, R^(6a) and R^(7a) together with the common nitrogen    to which they are both attached, may form an optionally substituted    N-heteroaryl or an optionally substituted N-heterocyclyl;-   each R⁸ is independently selected from the group consisting of a    direct bond and an optionally substituted straight or branched    alkylene chain; and-   each R⁹ is an optionally substituted straight or branched alkylene    chain.

One embodiment of the compounds of formula (Ia-1), as set forth above,is a compound according to formula (Ia-1a):

wherein:

-   n is 0 or 1;-   R^(2a) is independently selected from the group consisting of    hydrogen, optionally substituted alkyl, halo, cyano and —OR⁶;-   R³, when present, is independently selected from the group    consisting of alkyl, halo and haloalkyl;-   R⁴ is selected from the group consisting of phenyl, benzimidazolyl,    benzo[b][1,4]oxazinyl, benzo[b]azepinyl,    2,3,4,5-tetrahydro-1H-benzo[b]azepinyl,    3,4-dihydro-2H-benzo[b][1,4]thiazinyl,    3′,4′-dihydrospiro[cyclobutane-1,2′-pyrido[3,2-b][1,4]oxazinyl,    3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl,    3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazinyl, imidazo[1,2-a]pyridinyl,    6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indolyl,    7,8,9,9a-tetrahydro-5H-pyrido[2,3-e]pyrrolo[1,2-a][1,4]diazepin-10(11H)-onyl,    indolyl, indolinyl, naphthyridinyl, pyrazolyl, pyridinyl, pyrazinyl,    pyrimidinyl, pyrrolyl, 1H-pyrrolo[2,3-b]pyridinyl, and thiazolyl,    each optionally substituted by one or more substituents    independently selected from the group consisting of oxo, alkyl,    halo, haloalkyl, cyano, N-heterocyclyl, N-heteroaryl, aryl,    —R⁸—OR^(6a), —R⁸—S(O)_(p)R^(6a) (where p is 0, 1 or 2),    —R⁸—C(O)R^(6a), —R⁸—C(O)OR^(6a), —R⁸—C(O)N(R^(6a))R^(7a),    —R⁸—N(R^(6a))R^(7a), —R⁸—N(R^(6a)—R⁹—N(R^(6a))R^(7a),    —R⁸—N(R^(6a))—R⁹—OR^(7a), —R⁸—N(R^(6a))C(O)R^(7a),    —R⁸—N(R^(6a))S(O)₂R^(7a), —R⁸—N(R^(6a))C(O)—R⁸—N(R^(6a))R^(7a), and    —R⁸—N(R^(6a))—R⁹—N(R^(6a))S(O)₂R^(7a), where the N-heterocyclyl, the    N-heteroaryl and the aryl are each independently optionally    substituted by one or more substituents selected from the group    consisting of —C(O)R⁶, —R⁸—N(R⁶)R⁷, —R⁸—C(O)N(R⁶)R⁷, alkyl, halo and    optionally substituted aryl;-   R^(5a) is selected from the group consisting of hydrogen, alkyl,    alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, optionally    substituted aryl, optionally substituted aralkyl, optionally    substituted aralkenyl, optionally substituted aralkynyl, optionally    substituted cycloalkyl, optionally substituted cycloalkylalkyl,    optionally substituted cycloalkylalkenyl, optionally substituted    cycloalkylalkynyl, optionally substituted heterocyclyl, optionally    substituted heterocyclylalkyl, optionally substituted    heterocyclylalkenyl, optionally substituted heterocyclylalkynyl,    optionally substituted heteroaryl, optionally substituted    heteroarylalkyl, optionally substituted heteroarylalkenyl,    optionally substituted heteroarylalkynyl, —R⁸—OR⁶, —R⁸—C(O)R⁶,    —R⁸—C(O)OR⁶, —R⁹—N(R⁶)R⁷, —R⁸—C(O)N(R⁶)R⁷, —R⁸—C(N═R⁶)N(R⁶)R⁷,    —R⁸—S(O)₂N(R⁶)R⁷, and —R⁸—S(O)_(t)R⁶ (where t is 1 or 2);-   each R⁶ and each R⁷ is independently selected from the group    consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl,    haloalkenyl, haloalkynyl, optionally substituted cycloalkyl,    optionally substituted cycloalkylalkyl, optionally substituted aryl,    optionally substituted aralkyl, optionally substituted aralkenyl,    optionally substituted aralkynyl, optionally substituted    heterocyclyl, optionally substituted heterocyclylalkyl, optionally    substituted heterocyclylalkenyl, optionally substituted    heterocyclylalkynyl, optionally substituted heteroaryl, optionally    substituted heteroarylalkyl, optionally substituted    heteroarylalkenyl, and optionally substituted heteroarylalkynyl; or    any R⁶ and R⁷, together with the common nitrogen to which they are    both attached, form an optionally substituted N-heteroaryl or an    optionally substituted N-heterocyclyl;-   R^(6a) and R^(7a) are each independently selected from the group    consisting of hydrogen, alkyl, optionally substituted cycloalkyl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, optionally substituted heteroaryl, and optionally    substituted aralkyl, and when any R^(6a) and R^(7a) are bonded to a    common nitrogen, R^(6a) and R^(7a) together with the common nitrogen    to which they are both attached, may form an optionally substituted    N-heteroaryl or an optionally substituted N-heterocyclyl;-   each R⁸ is independently selected from the group consisting of a    direct bond and an optionally substituted straight or branched    alkylene chain; and-   each R⁹ is an optionally substituted straight or branched alkylene    chain.

Of this embodiment, one embodiment is a compound of formula (Ia-1a), asset forth above, wherein:

-   n is 0 or 1;-   R^(2a) is independently selected from the group consisting of    hydrogen, optionally substituted alkyl, halo, cyano and —OR⁶;-   R³, when present, is independently selected from the group    consisting of alkyl, halo and haloalkyl;-   R⁴ is pyridinyl substituted by one or more substituents selected    from the group consisting of alkyl, haloalkyl, cyano, —R⁸—OR^(6a),    —R⁸—N(R^(6a))R^(7a), —R⁸—N(R^(6a))—R⁹—N(R^(6a))R^(7a) and    —R⁸—N(R^(6a))—R⁹—OR^(7a);-   R^(5a) is independently selected from the group consisting of    hydrogen, alkyl, optionally substituted cycloalkyl, —R⁸—C(O)R⁶ and    —R⁸—S(O)_(t)R⁶ (where t is 1 or 2);-   each R⁶ is independently selected from the group consisting of    hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl,    haloalkynyl, optionally substituted cycloalkyl, optionally    substituted cycloalkylalkyl, optionally substituted aryl, optionally    substituted aralkyl, optionally substituted aralkenyl, optionally    substituted aralkynyl, optionally substituted heterocyclyl,    optionally substituted heterocyclylalkyl, optionally substituted    heterocyclylalkenyl, optionally substituted heterocyclylalkynyl,    optionally substituted heteroaryl, optionally substituted    heteroarylalkyl, optionally substituted heteroarylalkenyl, and    optionally substituted heteroarylalkynyl;-   R^(6a) and R^(7a) are each independently selected from the group    consisting of hydrogen, alkyl, optionally substituted cycloalkyl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, optionally substituted heteroaryl, and optionally    substituted aralkyl, and when any R^(6a) and R^(7a) are bonded to a    common nitrogen, R^(6a) and R^(7a) together with the common nitrogen    to which they are both attached, may form an optionally substituted    N-heteroaryl or an optionally substituted N-heterocyclyl;-   each R⁸ is independently selected from the group consisting of a    direct bond and an optionally substituted straight or branched    alkylene chain; and-   each R⁹ is an optionally substituted straight or branched alkylene    chain.

A specific embodiment of this embodiment is a compound of formula(Ia-1a), as set forth above, selected from the group consisting of:

-   4-(6-(N,N-dimethylamino)pyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(N,N-dimethylamino)pyridin-3-yl)-5-methyl-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(N,N-dimethylamino)pyridin-3-yl)-5-trifluoromethyl-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(N,N-dimethylamino)pyridin-3-yl)-5-fluoro-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(N,N-dimethylamino)pyridin-3-yl)-5-fluoro-N-(3-fluoro-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(N,N-dimethylamino)pyridin-3-yl)-5-methyl-N-(3-fluoro-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(N,N-dimethylamino)pyridin-3-yl)-N-(3-fluoro-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(dimethylamino)pyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-ethyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(2-(morpholin-4-yl)ethyl)aminopyridin-3-yl)-N-(4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(2-(morpholin-4-yl)ethyl)aminopyridin-3-yl)-N-(3-fluoro-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(cyclohexylamino)pyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(cyclohexylamino)pyridin-3-yl)-N-(3-fluoro-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(benzylamino)pyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(benzylamino)pyridin-3-yl)-N-(3-fluoro-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(cyclohexylamino)pyridin-3-yl)-N-(3-trifluoromethyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(dimethylamino)pyridin-3-yl)-N-(3-trifluoromethyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-cyanopyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(5-cyanopyridin-3-yl)-N-(3-methyl-4((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-aminopyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-ethylcarbonyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-aminopyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-methylsulfonyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-ethoxypyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-ethoxypyridin-3-yl)-N-(3-fluoro-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(dimethylamino)pyridin-3-yl)-N-(4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(3-ethoxypropyl)aminopyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(propylamino)pyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(2-(morpholin-4-yl)ethyl)aminopyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-ethylcarbonyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(3-dimethylamino)propylaminopyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(3-methylbutyl)aminopyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(3,3-dimethylbutyl)aminopyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(2-methoxyethyl)(methyl)aminopyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(propylamino)pyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-methylsulfonyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(2-(trifluoromethyl)pyridin-4-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(tetrahydropyran-4-yloxy)pyridin-3-yl)-N-(3-chloro-4-((1S,4S)-5-(methylsulfonyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(tetrahydropyran-4-yloxy)pyridin-3-yl)-N-(3-chloro-4-((1S,4S)-5-acetyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(tetrahydropyran-4-yloxy)pyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;    and-   4-(6-(tetrahydropyran-4-yloxy)pyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-cyclopentyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine.

Of this embodiment, another embodiment is a compound of formula (Ia-1a),as set forth above, wherein:

-   n is 0 or 1;-   R^(2a) is independently selected from the group consisting of    hydrogen, optionally substituted alkyl, halo, cyano and —OR⁶;-   R³, when present, is independently selected from the group    consisting of alkyl, halo and haloalkyl;-   R⁴ is pyridinyl substituted by an N-heterocyclyl selected from the    group consisting of morpholinyl, piperazinyl, piperidinyl,    oxazepanyl, 5-oxa-2-azabicyclo[2.2.1]heptanyl and thiamorpholinyl,    where the N-heterocyclyl is optionally substituted by one or more    substituents selected from the group consisting of —C(O)R⁶,    —R⁸—N(R⁶)R⁷, —R⁸—C(O)N(R⁶)R⁷, alkyl, halo and optionally substituted    aryl;-   R^(5a) is independently selected from the group consisting of    hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl,    optionally substituted cycloalkylalkyl, —R⁸—C(O)R⁶, —R⁸—C(O)N(R⁶)R⁷,    —R⁸—C(N═R⁶)N(R⁶)R⁷ and —R⁸—S(O)_(t)R⁸ (where t is 1 or 2);-   each R⁶ and each R⁷ is independently selected from the group    consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl,    haloalkenyl, haloalkynyl, optionally substituted cycloalkyl,    optionally substituted cycloalkylalkyl, optionally substituted aryl,    optionally substituted aralkyl, optionally substituted aralkenyl,    optionally substituted aralkynyl, optionally substituted    heterocyclyl, optionally substituted heterocyclylalkyl, optionally    substituted heterocyclylalkenyl, optionally substituted    heterocyclylalkynyl, optionally substituted heteroaryl, optionally    substituted heteroarylalkyl, optionally substituted    heteroarylalkenyl, and optionally substituted heteroarylalkynyl; or    any R⁶ and R⁷, together with the common nitrogen to which they are    both attached, form an optionally substituted N-heteroaryl or an    optionally substituted N-heterocyclyl; and-   each R⁸ is independently selected from the group consisting of a    direct bond and an optionally substituted straight or branched    alkylene chain.

A specific embodiment of this embodiment is a compound of formula(Ia-1a), as set forth above, selected from the group consisting of:

-   4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-fluoro-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(4-acetylpiperazin-1-yl)pyridin-3-yl)-N-(3-fluoro-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-ethyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-((ethylamino)carbonyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-(2,2,2-trifluoroethyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-(cyclopropyl)methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(3-fluoro-2-(morpholin-4-yl)pyridin-4-yl)-N-(3-fluoro-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(5-methyl-6-(morpholin-4-yl)pyridin-3-yl)-N-(3-fluoro-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(5-methyl-6-(morpholin-4-yl)pyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   5-methyl-4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   5-methyl-4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-fluoro-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-methyl-4-((1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-fluoro-4-((1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-trifluoromethyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-cyano-4-((1S,4S)-5-acetyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-cyano-4-((1S,4S)-5-methylsulfonyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-cyano-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-cyano-4-((1S,4S)-5-cyclopentyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(cis-2,6-dimethylmorpholin-4-yl)pyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(2-(dimethylamino)methylmorpholin-4-yl)pyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(piperidin-1-yl)pyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(3-(aminocarbonyl)piperidin-1-yl)pyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-methylsulfonyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-ethylcarbonyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-amidino-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-isobutyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(1,4-oxazepan-4-yl)pyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)pyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(thiamorpholin-4-yl)pyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;    and-   4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-cyclopropyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-chloro-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-chloro-4-((1S,4S)-5-(methylsulfonyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-chloro-4-((1S,4S)-5-acetyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-chloro-4-((1S,4S)-5-(1-methylethyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)pyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-(methylsulfonyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;    and-   4-(6-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)pyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine.

Another embodiment is a compound of formula (Ia-1a), as set forth above,wherein:

-   n is 0 or 1;-   R^(2a) is independently selected from the group consisting of    hydrogen, optionally substituted alkyl, halo, cyano and —OR⁶;-   R³, when present, is independently selected from the group    consisting of alkyl, halo and haloalkyl;-   R⁴ is pyridinyl substituted by one or more substituents selected    from the group consisting of —R⁸—C(O)R^(6a), —R⁸—C(O)OR^(6a),    —R⁸—C(O)N(R^(6a))R^(7a), —R⁸—S(O)_(p)R^(6a) (where p is 0, 1 or 2),    —R⁸—N(R^(6a))—R⁹—N(R^(6a))S(O)₂R^(7a), —R⁸—N(R^(6a))C(O)R^(7a),    —R⁸—N(R^(6a))S(O)₂R^(7a), —R⁸—N(R^(6a))C(O)—R⁸—N(R^(6a))R^(7a) and    tetrazolyl;-   R^(5a) is independently selected from the group consisting of    hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl,    optionally substituted cycloalkylalkyl, —R⁸—C(O)R⁶, —R⁸—C(O)N(R⁶)R⁷,    —R⁸—C(N═R⁶)N(R⁶)R⁷ and —R⁸—S(O)_(t)R⁶ (where t is 1 or 2);-   each R⁶ and each R⁷ is independently selected from the group    consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl,    haloalkenyl, haloalkynyl, optionally substituted cycloalkyl,    optionally substituted cycloalkylalkyl, optionally substituted aryl,    optionally substituted aralkyl, optionally substituted aralkenyl,    optionally substituted aralkynyl, optionally substituted    heterocyclyl, optionally substituted heterocyclylalkyl, optionally    substituted heterocyclylalkenyl, optionally substituted    heterocyclylalkynyl, optionally substituted heteroaryl, optionally    substituted heteroarylalkyl, optionally substituted    heteroarylalkenyl, and optionally substituted heteroarylalkynyl; or    any R⁶ and R⁷, together with the common nitrogen to which they are    both attached, form an optionally substituted N-heteroaryl or an    optionally substituted N-heterocyclyl;-   R^(6a) and R^(7a) are each independently selected from the group    consisting of hydrogen, alkyl, optionally substituted cycloalkyl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, optionally substituted heteroaryl, and optionally    substituted aralkyl, and when any R^(6a) and R^(7a) are bonded to a    common nitrogen, R^(6a) and R^(7a) together with the common nitrogen    to which they are both attached, may form an optionally substituted    N-heteroaryl or an optionally substituted N-heterocyclyl;-   each R⁸ is independently selected from the group consisting of a    direct bond and an optionally substituted straight or branched    alkylene chain; and-   R⁹ is an optionally substituted straight or branched alkylene chain.

A specific embodiment of this embodiment is a compound of formula(Ia-1a), as set forth above, selected from the group consisting of:

-   4-(6-(methylaminocarbonyl)pyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(5-((morpholin-4-yl)carbonyl)pyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine.    Bis TFA salt;-   4-(5-(methyl)sulfonylpyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-((2-(cyclopropylsulfonyl)aminoethyl)-amino)pyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(1H-tetrazol-5-yl)pyridin-3-yl)-N-(3-methyl-4((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine-   4-(6-(acetamido)pyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(2-(morpholin-4-yl)acetamido)pyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(2-(morpholin-4-yl)acetamido)pyridin-3-yl)-N-(4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(2-(morpholin-4-yl)acetamido)pyridin-3-yl)-N-(3-fluoro-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(acetamido)pyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-ethylcarbonyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(methylsulfonylamino)pyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(2-(dimethylamino)acetamido)-pyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;    and-   4-(6-(methylsulfonylamino)pyridin-3-yl)-N-(3-fluoro-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;    and-   4-(5-(1-methylethoxy)carbonylpropyl-6-aminopyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine.

Another embodiment is a compound of formula (Ia-1a), as set forth above,wherein:

-   n is 0 or 1;-   R^(2a) is independently selected from the group consisting of    hydrogen, optionally substituted alkyl, halo, cyano and —OR⁶;-   R³, when present, is independently selected from the group    consisting of alkyl, halo and haloalkyl;-   R⁴ is selected from the group consisting of naphthyridinyl,    benzo[b]azepinyl, 2,3,4,5-tetrahydro-1H-benzo[b]azepinyl,    benzo[b][1,4]oxazinyl, 3,4-dihydro-2H-benzo[b][1,4]thiazinyl,    3′,4′-dihydrospiro[cyclobutane-1,2′-pyrido[3,2-b][1,4]oxazinyl,    3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazinyl,    6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indolyl,    7,8,9,9a-tetrahydro-5H-pyrido[2,3-e]pyrrolo[1,2-a][1,4]diazepin-10(11H)-onyl,    and 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl, each optionally    substituted by one or more substituents independently selected from    the group consisting of alkyl and oxo;-   R^(5a) is independently selected from the group consisting of    hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl,    optionally substituted cycloalkylalkyl, —R⁸—C(O)R⁶, —R⁸—C(O)N(R⁶)R⁷,    —R⁸—C(N═R⁶)N(R⁶)R⁷, —R⁸—S(O)_(t)R⁶ (where t is 1 or 2), and    —R⁸—S(O)₂N(R⁶)R⁷;-   each R⁶ and each R⁷ is independently selected from the group    consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl,    haloalkenyl, haloalkynyl, optionally substituted cycloalkyl,    optionally substituted cycloalkylalkyl, optionally substituted aryl,    optionally substituted aralkyl, optionally substituted aralkenyl,    optionally substituted aralkynyl, optionally substituted    heterocyclyl, optionally substituted heterocyclylalkyl, optionally    substituted heterocyclylalkenyl, optionally substituted    heterocyclylalkynyl, optionally substituted heteroaryl, optionally    substituted heteroarylalkyl, optionally substituted    heteroarylalkenyl, and optionally substituted heteroarylalkynyl; or    any R⁶ and R⁷, together with the common nitrogen to which they are    both attached, form an optionally substituted N-heteroaryl or an    optionally substituted N-heterocyclyl; and-   each R⁸ is independently selected from the group consisting of a    direct bond and an optionally substituted straight or branched    alkylene chain.

A specific embodiment of this embodiment is a compound of formula(Ia-1a), as set forth above, selected from the group consisting of:

-   4-(4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(3-fluoro-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(3-fluoro-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(3-methyl-4-((1S,4S)-5-(ethylcarbonyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(3-methyl-4-((1S,4S)-5-(methylsulfonyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(3-methyl-4-((1S,4S)-5-ethyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(3′-oxo-3,4′-dihydrospiro[cyclobutane-1,2′-pyrido[3,2-b][1,4]oxazine]-7′-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(3-oxo-3,4′-dihydrospiro[cyclobutane-1,2′-pyrido[3,2-b][1,4]oxazine]-7′-yl)-N-(3-methyl-4-((1S,4S)-5-ethyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(3-methyl-4-((1S,4S)-5-(aminosulfonyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(7-oxo-5,6,7,8-tetahydro-1,8-naphthyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(3-cyano-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(3-methyl-4-((1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(3-fluoro-4-((1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(3-fluoro-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(3-trifluoromethyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(2H-benzo[b][1,4]oxazin-3(4H)-on-6-yl)-N-(3-fluoro-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(2,2,4-trimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(2,2,4-trimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(3-fluoro-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(3-trifluoromethyl-4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(3-methyl-4-((1S,4S)-5-methylsulfonyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-methylsulfonyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-7-yl)-N-(4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-N-(3-methyl-4-((1S,4S)-5-methylsulfonyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-yl)-N-(3-methyl-4-((1S,4S)-5-methylsulfonyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(3-methyl-4-((1S,4S)-5-(1-methylethyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(3-methyl-4-((1S,4S)-5-cyclopropyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(3-chloro-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(3-chloro-4-((1S,4S)-5-(methylsulfonyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(3-methyl-4-((1S,4S)-5-cyclopentyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(3-methyl-4-((1S,4S)-5-acetyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-3-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-3-yl)-N-(3-methyl-4-((1S,4S)-5-(methylsulfonyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(7,8,9,9a-tetrahydro-5H-pyrido[2,3-e]pyrrolo[1,2-a][1,4]diazepin-10(11H)-on-3-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-N-(3-cyano-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-yl)-N-(3-cyano-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-7-yl)-N-(3-cyano-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;    and-   4-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-7-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine.

Another embodiment is a compound of formula (Ia-1a), as set forth above,wherein:

-   n is 0 or 1;-   R^(2a) is independently selected from the group consisting of    hydrogen, optionally substituted alkyl, halo, cyano and —OR⁶;-   R³, when present, is independently selected from the group    consisting of alkyl, halo and haloalkyl;-   R⁴ is phenyl substituted by one or more substituents selected from    the group consisting of alkyl, haloalkyl, —R⁸—OR^(6a),    —R⁸—N(R^(6a))R^(7a), —R⁸—C(O)N(R^(6a))R^(7a),    —R⁸—N(R^(6a))C(O)R^(7a), —R⁸—N(R^(6a))S(O)₂R^(7a),    —R⁸—N(R^(6a))C(O)—R⁸—N(R^(6a))R^(7a), N-heteroaryl and    N-heterocyclyl, where the N-heterocyclyl and the N-heteroaryl are    each independently optionally substituted by one or more    substituents selected from the group consisting of —C(O)R⁶,    —R⁸—N(R⁶)R⁷, —R⁸—C(O)N(R⁶)R⁷, alkyl, halo and optionally substituted    aryl;-   R^(5a) is independently selected from the group consisting of    hydrogen, alkyl, —R⁸—C(O)R⁶ and —R⁸—S(O)_(t)R⁶ (where t is 1 or 2);-   each R⁶ and each R⁷ is independently selected from the group    consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl,    haloalkenyl, haloalkynyl, optionally substituted cycloalkyl,    optionally substituted cycloalkylalkyl, optionally substituted aryl,    optionally substituted aralkyl, optionally substituted aralkenyl,    optionally substituted aralkynyl, optionally substituted    heterocyclyl, optionally substituted heterocyclylalkyl, optionally    substituted heterocyclylalkenyl, optionally substituted    heterocyclylalkynyl, optionally substituted heteroaryl, optionally    substituted heteroarylalkyl, optionally substituted    heteroarylalkenyl, and optionally substituted heteroarylalkynyl; or    any R⁶ and R⁷, together with the common nitrogen to which they are    both attached, form an optionally substituted N-heteroaryl or an    optionally substituted N-heterocyclyl;-   R^(6a) and R^(7a) are each independently selected from the group    consisting of hydrogen, alkyl, optionally substituted cycloalkyl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, optionally substituted heteroaryl, and optionally    substituted aralkyl, and when any R^(6a) and R^(7a) are bonded to a    common nitrogen, R^(6a) and R^(7a) together with the common nitrogen    to which they are both attached, may form an optionally substituted    N-heteroaryl or an optionally substituted N-heterocyclyl;-   each R⁸ is independently selected from the group consisting of a    direct bond and an optionally substituted straight or branched    alkylene chain.

A specific embodiment of this embodiment is a compound of formula(Ia-1a), as set forth above, selected from the group consisting of:

-   4-(4-(N,N-dimethylamino)phenyl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(4-(N,N-dimethylamino)phenyl)-N-(3-fluoro-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(4-(4,5-dihydrothiazol-2-ylcarbamoyl)phenyl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(4-(1,1-dimethylethyl)phenyl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(4-(morpholin-4-yl)phenyl)-N-(3-fluoro-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine.TFA    salt;-   4-(4-((methyl)aminocarbonylmethyl)-phenyl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine.TFA    salt;-   4-(4-((cyclopropyl)aminocarbonyl-methyl)phenyl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(4-(5-(4-dimethylaminophenyl)oxazol-2-yl)phenyl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(4-(t-butylcarbonylamino)phenyl)-N-(3-fluoro-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(4-(t-butylcarbonylamino)phenyl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(4-((pyridin-2-yl)aminocarbonyl)phenyl)-N-(3-fluoro-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(4-((pyridin-2-yl)aminocarbonyl)phenyl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(4-(methylsulfonylamino)phenyl)-N-(3-fluoro-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(4-(methylsulfonylamino)phenyl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(4-(3-cyclopropylureido)phenyl)-N-(4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(4-(1-ethoxyethyl)phenyl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(4-(1-ethoxyethyl)phenyl)-N-(3-fluoro-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;    and-   4-(4-(trifluoromethyl)phenyl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine.

Another embodiment is a compound of formula (Ia-1a), as set forth above,wherein:

-   n is 0 or 1;-   R^(2a) is independently selected from the group consisting of    hydrogen, optionally substituted alkyl, halo, cyano and —OR⁶;-   R³, when present, is independently selected from the group    consisting of alkyl, halo and haloalkyl;-   R⁴ is selected from the group consisting of benzimidazolyl,    imidazo[1,2-a]pyridinyl, indolyl, indolinyl, pyrazolyl, pyrazinyl,    pyrimidinyl, pyrrolyl, 1H-pyrrolo[2,3-b]pyridinyl and thiazolyl,    each independently substituted by one or more substituents selected    from the group consisting of alkyl, cyano, oxo, —R⁸—OR^(6a),    —R⁸—N(R^(6a))R^(7a), —R⁸—C(O)N(R^(6a))R^(7a),    —R⁸—N(R^(6a))C(O)R^(7a), —R⁸—N(R^(6a))S(O)₂R^(7a),    —R⁸—N(R^(6a))C(O)—R⁸—N(R^(6a))R^(7a), aryl, N-heteroaryl and    N-heterocyclyl, where the aryl, the N-heterocyclyl and the    N-heteroaryl are each independently optionally substituted by one or    more substituents selected from the group consisting of —C(O)R⁶,    —R⁸—N(R⁶)R⁷, —R⁸—C(O)N(R⁶)R⁷, alkyl, halo and optionally substituted    aryl;-   R^(5a) is independently selected from the group consisting of    hydrogen, alkyl, —R⁸—C(O)R⁶ and —R⁸—S(O)_(t)R⁶ (where t is 1 or 2);-   each R⁶ and each R⁷ is independently selected from the group    consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl,    haloalkenyl, haloalkynyl, optionally substituted cycloalkyl,    optionally substituted cycloalkylalkyl, optionally substituted aryl,    optionally substituted aralkyl, optionally substituted aralkenyl,    optionally substituted aralkynyl, optionally substituted    heterocyclyl, optionally substituted heterocyclylalkyl, optionally    substituted heterocyclylalkenyl, optionally substituted    heterocyclylalkynyl, optionally substituted heteroaryl, optionally    substituted heteroarylalkyl, optionally substituted    heteroarylalkenyl, and optionally substituted heteroarylalkynyl; or    any R⁶ and R⁷, together with the common nitrogen to which they are    both attached, form an optionally substituted N-heteroaryl or an    optionally substituted N-heterocyclyl;-   R^(6a) and R^(7a) are each independently selected from the group    consisting of hydrogen, alkyl, optionally substituted cycloalkyl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, optionally substituted heteroaryl, and optionally    substituted aralkyl, and when any R^(6a) and R^(7a) are bonded to a    common nitrogen, R^(6a) and R^(7a) together with the common nitrogen    to which they are both attached, may form an optionally substituted    N-heteroaryl or an optionally substituted N-heterocyclyl; and-   each R⁸ is independently selected from the group consisting of a    direct bond and an optionally substituted straight or branched    alkylene chain.

A specific embodiment of this embodiment is a compound of formula(Ia-1a), as set forth above, selected from the group consisting of:

-   4-(1H-indol-6-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(1H-pyrrolo[2,3-b]pyridin-5-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(1H-pyrrolo[2,3-b]pyridin-5-yl)-N-(3-fluoro-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(1H-pyrrolo[2,3-b]pyridin-5-yl)-N-(3-methyl-4-((1S,4S)-5-(2,2,2-trifluoroethyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(1H-pyrrolo[2,3-b]pyridin-5-yl)-N-(3-methyl-4-((1S,4S)-5-(cyclopropyl)methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(2-(morpholin-4-yl)pyrimidin-5-yl)-N-(4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(2-(morpholin-4-yl)pyrimidin-5-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(2-(morpholin-4-yl)pyrimidin-5-yl)-N-(3-fluoro-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(2-((cyclopropyl)carbonylamino)-pyrimidin-5-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(2-(propyl)aminopyrimidin-5-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(2-(propyl)aminopyrimidin-5-yl)-N-(3-fluoro-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(imidazo[1,2-a]pyridin-6-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-methoxy-1H-indol-2-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(1-(3-chlorophenyl)-1H-pyrazol-4-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(1-methylbenzimidazol-6-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(5-cyano-1H-indol-2-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(2-oxoindolin-5-yl)-N-(3-methyl-4((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(5-(3-methylpiperidin-1-yl)pyrazin-2-yl)-N-(3-fluoro-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(2-(diethylamino)thiazol-4-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(2-(diethylamino)thiazol-4-yl)-N-(3-fluoro-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(1H-pyrrol-3-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(1H-pyrrol-3-yl)-N-(4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(1H-pyrrol-3-yl)-N-(3-trifluoromethyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(2-(dimethylamino)thiazol-4-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(2-(dimethylamino)thiazol-4-yl)-N-(3-fluoro-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(5-(morpholin-4-yl)pyrazin-2-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(5-(morpholin-4-yl)pyrazin-2-yl)-N-(3-fluoro-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(1-(pyridin-4-yl)-1H-indol-5-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(1-(pyridin-4-yl)-1H-indol-5-yl)-N-(3-fluoro-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(1-(pyridin-4-yl)-1H-indol-5-yl)-N-(3-methyl-4-((1S,4S)-5-ethyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;    and-   4-(1-(pyridin-4-yl)-1H-indol-5-yl)-N-(3-methyl-4-((1S,4S)-5-isobutyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine.

Another embodiment of the compounds of formula (Ia-1), as set forthabove, is a compound according to formula (Ia-1b):

wherein:

-   n is 0 or 1;-   R^(2a) is independently selected from the group consisting of    hydrogen, optionally substituted alkyl, halo, cyano and —OR⁶;-   R³, when present, is independently selected from the group    consisting of alkyl, halo and haloalkyl;-   R⁴ is selected from the group consisting of phenyl, benzimidazolyl,    benzo[b][1,4]oxazinyl, benzo[b]azepinyl,    2,3,4,5-tetrahydro-1H-benzo[b]azepinyl,    3,4-dihydro-2H-benzo[b][1,4]thiazinyl,    3′,4′-dihydrospiro[cyclobutane-1,2′-pyrido[3,2-b][1,4]oxazinyl,    3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl,    3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazinyl, imidazo[1,2-a]pyridinyl,    6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indolyl,    7,8,9,9a-tetrahydro-5H-pyrido[2,3-e]pyrrolo[1,2-a][1,4]diazepin-10(11H)-onyl,    indolyl, indolinyl, naphthyridinyl, pyrazolyl, pyridinyl, pyrazinyl,    pyrimidinyl, pyrrolyl, 1H-pyrrolo[2,3-b]pyridinyl, and thiazolyl,    each optionally substituted by one or more substituents    independently selected from the group consisting of oxo, alkyl,    halo, haloalkyl, cyano, N-heterocyclyl, N-heteroaryl, aryl,    —R⁸—OR^(6a), —R⁸—S(O)_(p)R^(6a) (where p is 0, 1 or 2),    —R⁸—C(O)R^(6a), —R⁸—C(O)OR^(6a), —R⁸—C(O)N(R^(6a))R^(7a),    —R⁸—N(R^(6a))R^(7a), —R⁸—N(R^(6a))—R⁹—N(R^(6a))R^(7a),    —R⁸—N(R^(6a))—R⁹—OR^(7a), —R⁸—N(R^(6a))C(O)R^(7a),    —R⁸—N(R^(6a))S(O)₂R^(7a), —R⁸—N(R^(6a))C(O)—R⁸—N(R^(6a))R^(7a), and    —R⁸—N(R^(6a))—R⁹—N(R^(6a))S(O)₂R^(7a), where the N-heterocyclyl, the    N-heteroaryl and the aryl are each independently optionally    substituted by one or more substituents selected from the group    consisting of —C(O)R⁶, —R⁸—N(R⁶)R⁷, —R⁸—C(O)N(R⁶)R⁷, alkyl, halo and    optionally substituted aryl;-   each R⁶ and each R⁷ is independently selected from the group    consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl,    haloalkenyl, haloalkynyl, optionally substituted cycloalkyl,    optionally substituted cycloalkylalkyl, optionally substituted aryl,    optionally substituted aralkyl, optionally substituted aralkenyl,    optionally substituted aralkynyl, optionally substituted    heterocyclyl, optionally substituted heterocyclylalkyl, optionally    substituted heterocyclylalkenyl, optionally substituted    heterocyclylalkynyl, optionally substituted heteroaryl, optionally    substituted heteroarylalkyl, optionally substituted    heteroarylalkenyl, and optionally substituted heteroarylalkynyl; or    any R⁶ and R⁷, together with the common nitrogen to which they are    both attached, form an optionally substituted N-heteroaryl or an    optionally substituted N-heterocyclyl;-   R^(6a) and R^(7a) are each independently selected from the group    consisting of hydrogen, alkyl, optionally substituted cycloalkyl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, optionally substituted heteroaryl, and optionally    substituted aralkyl, and when any R^(6a) and R^(7a) are bonded to a    common nitrogen, R^(6a) and R^(7a) together with the common nitrogen    to which they are both attached, may form an optionally substituted    N-heteroaryl or an optionally substituted N-heterocyclyl;-   each R⁸ is independently selected from the group consisting of a    direct bond and an optionally substituted straight or branched    alkylene chain; and-   each R⁹ is an optionally substituted straight or branched alkylene    chain.

Of this embodiment, one embodiment is a compound of formula (I-1b), asset forth above, wherein:

-   n is 0 or 1;-   R^(2a) is independently selected from the group consisting of    hydrogen, optionally substituted alkyl, halo, cyano and —OR⁶;-   R³, when present, is independently selected from the group    consisting of alkyl, halo and haloalkyl;-   R⁴ is pyridinyl substituted by one or more substituents selected    from the group consisting of alkyl, cyano, —R⁸—OR^(6a),    —R⁸—N(R^(6a))R^(7a), —R⁸—N(R^(6a))—R⁹—N(R^(6a))R^(7a) and    —R⁸—N(R^(6a))—R⁹—OR^(7a);-   R⁶ is selected from the group consisting of hydrogen, alkyl,    alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, optionally    substituted cycloalkyl, optionally substituted cycloalkylalkyl,    optionally substituted aryl, optionally substituted aralkyl,    optionally substituted aralkenyl, optionally substituted aralkynyl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, optionally substituted heterocyclylalkenyl,    optionally substituted heterocyclylalkynyl, optionally substituted    heteroaryl, optionally substituted heteroarylalkyl, optionally    substituted heteroarylalkenyl, and optionally substituted    heteroarylalkynyl;-   R^(6a) and R^(7a) are each independently selected from the group    consisting of hydrogen, alkyl, optionally substituted cycloalkyl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, optionally substituted heteroaryl, and optionally    substituted aralkyl, and when any R^(6a) and R^(7a) are bonded to a    common nitrogen, R^(6a) and R^(7a) together with the common nitrogen    to which they are both attached, may form an optionally substituted    N-heteroaryl or an optionally substituted N-heterocyclyl;-   each R⁸ is independently selected from the group consisting of a    direct bond and an optionally substituted straight or branched    alkylene chain; and-   each R⁹ is an optionally substituted straight or branched alkylene    chain.

A specific embodiment of this embodiment is a compound of formula(Ia-1b), as set forth above, selected from the group consisting of:

-   4-(6-(3-ethoxypropyl)aminopyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-oxa-2-azabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(propylamino)pyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-oxa-2-azabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(3-dimethylamino)propylaminopyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-oxa-2-azabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;    and-   4-(6-(2-methoxyethyl)(methyl)aminopyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-oxa-2-azabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine.

Another embodiment is a compound of formula (I-1b) wherein:

-   n is 0 or 1;-   R^(2a) is independently selected from the group consisting of    hydrogen, optionally substituted alkyl, halo, cyano and —OR⁶;-   R³, when present, is independently selected from the group    consisting of alkyl, halo and haloalkyl;-   R⁴ is pyridinyl substituted by an N-heterocyclyl selected from the    group consisting of morpholinyl, piperazinyl, piperidinyl,    pyrrolidinyl, oxazepanyl, 5-oxa-2-azabicyclo[2.2.1]heptanyl and    thiamorpholinyl, where the N-heterocyclyl is optionally substituted    by one or more substituents selected from the group consisting of    —C(O)R⁶, —R⁸—N(R⁶)R⁷, —R⁸—C(O)N(R⁶)R⁷, alkyl, halo and optionally    substituted aryl;-   each R⁶ and each R⁷ is independently selected from the group    consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl,    haloalkenyl, haloalkynyl, optionally substituted cycloalkyl,    optionally substituted cycloalkylalkyl, optionally substituted aryl,    optionally substituted aralkyl, optionally substituted aralkenyl,    optionally substituted aralkynyl, optionally substituted    heterocyclyl, optionally substituted heterocyclylalkyl, optionally    substituted heterocyclylalkenyl, optionally substituted    heterocyclylalkynyl, optionally substituted heteroaryl, optionally    substituted heteroarylalkyl, optionally substituted    heteroarylalkenyl, and optionally substituted heteroarylalkynyl; or    any R⁶ and R⁷, together with the common nitrogen to which they are    both attached, form an optionally substituted N-heteroaryl or an    optionally substituted N-heterocyclyl; and-   each R⁸ is independently selected from the group consisting of a    direct bond and an optionally substituted straight or branched    alkylene chain.

A specific embodiment of this embodiment is a compound of formula(Ia-1b), as set forth above, selected from the group consisting of:

-   4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-oxa-2-azabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-cis-2,6-dimethylmorpholin-4-yl)pyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-oxa-2-azabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(1,4-oxazepan-4-yl)pyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-oxa-2-azabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;    and-   4-(6-((1S,4S)-5-oxa-2-azabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-oxa-2-azabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine.

Another embodiment is a compound of formula (Ia-1b), as set forth above,wherein:

-   n is 0 or 1;-   R^(2a) is independently selected from the group consisting of    hydrogen, optionally substituted alkyl, halo, cyano and —OR⁶;-   R³, when present, is independently selected from the group    consisting of alkyl, halo and haloalkyl;-   R⁴ is pyridinyl substituted by one or more substituents selected    from the group consisting of —R⁸—C(O)R^(6a),    —R⁸—C(O)N(R^(6a))R^(7a), —R⁸—S(O)_(p)R^(6a) (where p is 0, 1 or 2),    —R⁸—N(R^(6a))—R⁹—N(R^(6a))S(O)₂R^(7a), —R⁸—N(R^(6a))C(O)R^(7a),    —R⁸—N(R^(6a))S(O)₂R^(7a), —R⁸—N(R^(6a))C(O)—R⁸—N(R^(6a))R^(7a), and    tetrazolyl;-   R⁶ is selected from the group consisting of hydrogen, alkyl,    alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, optionally    substituted cycloalkyl, optionally substituted cycloalkylalkyl,    optionally substituted aryl, optionally substituted aralkyl,    optionally substituted aralkenyl, optionally substituted aralkynyl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, optionally substituted heterocyclylalkenyl,    optionally substituted heterocyclylalkynyl, optionally substituted    heteroaryl, optionally substituted heteroarylalkyl, optionally    substituted heteroarylalkenyl, and optionally substituted    heteroarylalkynyl;-   R^(6a) and R^(7a) are each independently selected from the group    consisting of hydrogen, alkyl, optionally substituted cycloalkyl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, optionally substituted heteroaryl, and optionally    substituted aralkyl, and when any R^(6a) and R^(7a) are bonded to a    common nitrogen, R^(6a) and R^(7a) together with the common nitrogen    to which they are both attached, may form an optionally substituted    N-heteroaryl or an optionally substituted N-heterocyclyl; and-   each R⁸ is independently selected from the group consisting of a    direct bond and an optionally substituted straight or branched    alkylene chain; and-   R⁹ is an optionally substituted straight or branched alkylene chain.

A specific embodiment of this embodiment is a compound of formula(Ia-1b), as set forth above, selected from the group consisting of:

-   4-(6-((2-(cyclopropylsulfonyl)aminoethyl)-amino)pyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-oxa-2-azabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(5-(methyl)sulfonylpyridin-3-yl)-N-(3-fluoro-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(5-(methyl)sulfonylpyridin-3-yl)-N-(3-trifluoromethyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;    and-   4-(6-(acetamido)pyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-oxa-2-azabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine.

Another embodiment is a compound of formula (Ia-1b), as set forth above,wherein:

-   n is 0 or 1;-   R^(2a) is independently selected from the group consisting of    hydrogen, optionally substituted alkyl, halo, cyano and —OR⁶;-   R³, when present, is independently selected from the group    consisting of alkyl, halo and haloalkyl;-   R⁴ is selected from the group consisting of naphthyridinyl,    benzo[b]azepinyl, benzo[b][1,4]oxazinyl,    3,4-dihydro-2H-benzo[b][1,4]thiazinyl,    3′,4′-dihydrospiro[cyclobutane-1,2′-pyrido[3,2-b][1,4]oxazinyl,    3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazinyl and    3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl, each optionally    substituted by one or more substituents independently selected from    the group consisting of alkyl and oxo; and-   R⁶ is selected from the group consisting of hydrogen, alkyl,    alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, optionally    substituted cycloalkyl, optionally substituted cycloalkylalkyl,    optionally substituted aryl, optionally substituted aralkyl,    optionally substituted aralkenyl, optionally substituted aralkynyl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, optionally substituted heterocyclylalkenyl,    optionally substituted heterocyclylalkynyl, optionally substituted    heteroaryl, optionally substituted heteroarylalkyl, optionally    substituted heteroarylalkenyl, and optionally substituted    heteroarylalkynyl;

A specific embodiment of this embodiment is a compound of formula(Ia-1b), as set forth above, selected from the group consisting of:

-   4-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(3-methyl-4-((1S,4S)-5-oxa-2-azabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(3-methyl-4-((1S,4S)-5-oxa-2-azabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;    and-   4-(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(3-methyl-4-((1S,4S)-5-oxa-2-azabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine.

Another embodiment is a compound of formula (Ia-1b), as set forth above,wherein:

-   n is 0 or 1;-   R^(2a) is independently selected from the group consisting of    hydrogen, optionally substituted alkyl, halo, cyano and —OR⁶;-   R³, when present, is independently selected from the group    consisting of alkyl, halo and haloalkyl;-   R⁴ is selected from the group consisting of benzimidazolyl,    imidazo[1,2-a]pyridinyl, indolyl, indolinyl, pyrazolyl, pyridinyl,    pyrazinyl, pyrimidinyl, pyrrolyl, 1H-pyrrolo[2,3-b]pyridinyl and    thiazolyl, each independently substituted by one or more    substituents selected from the group consisting of alkyl, cyano,    oxo, —R⁸—OR^(6a), —R⁸—N(R^(6a))R^(7a), —R⁸—C(O)N(R^(6a))R^(7a),    —R⁸—N(R^(6a))C(O)R^(7a), —R⁸—N(R^(6a))S(O)₂R^(7a),    —R⁸—N(R^(6a))C(O)—R⁸—N(R^(6a))R^(7a), aryl, N-heteroaryl and    N-heterocyclyl, where the aryl, the N-heterocyclyl and the    N-heteroaryl are each independently optionally substituted by one or    more substituents selected from the group consisting of —C(O)R⁶,    —R⁸—N(R⁶)R⁷, —R⁸—C(O)N(R⁶)R⁷, alkyl, halo and optionally substituted    aryl;-   each R⁶ and each R⁷ is independently selected from the group    consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl,    haloalkenyl, haloalkynyl, optionally substituted cycloalkyl,    optionally substituted cycloalkylalkyl, optionally substituted aryl,    optionally substituted aralkyl, optionally substituted aralkenyl,    optionally substituted aralkynyl, optionally substituted    heterocyclyl, optionally substituted heterocyclylalkyl, optionally    substituted heterocyclylalkenyl, optionally substituted    heterocyclylalkynyl, optionally substituted heteroaryl, optionally    substituted heteroarylalkyl, optionally substituted    heteroarylalkenyl, and optionally substituted heteroarylalkynyl; or    any R⁶ and R⁷, together with the common nitrogen to which they are    both attached, form an optionally substituted N-heteroaryl or an    optionally substituted N-heterocyclyl;-   R^(6a) and R^(7a) are each independently selected from the group    consisting of hydrogen, alkyl, optionally substituted cycloalkyl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, optionally substituted heteroaryl, and optionally    substituted aralkyl, and when any R^(6a) and R^(7a) are bonded to a    common nitrogen, R^(6a) and R^(7a) together with the common nitrogen    to which they are both attached, may form an optionally substituted    N-heteroaryl or an optionally substituted N-heterocyclyl; and-   each R⁸ is independently selected from the group consisting of a    direct bond and an optionally substituted straight or branched    alkylene chain.

A specific embodiment of this embodiment is a compound of formula(Ia-1b), as set forth above, selected from the group consisting of:

-   4-(1H-pyrrolo[2,3-b]pyridin-5-yl)-N-(3-methyl-4-((1S,4S)-5-oxa-2-azabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;    and-   4-(2-(morpholin-4-yl)pyrimidin-5-yl)-N-(3-methyl-4-((1S,4S)-5-oxa-2-azabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine.

Another embodiment of the compounds of formula (Ia-1), as set forthabove, is a compound according to formula (Ia-1c):

wherein:

-   n is 0 or 1;-   R^(2a) is independently selected from the group consisting of    hydrogen, optionally substituted alkyl, halo, cyano and —OR⁶;-   R³, when present, is independently selected from the group    consisting of alkyl, halo and haloalkyl;-   R⁴ is selected from the group consisting of phenyl, benzimidazolyl,    benzo[b][1,4]oxazinyl, benzo[b]azepinyl,    2,3,4,5-tetrahydro-1H-benzo[b]azepinyl,    3,4-dihydro-2H-benzo[b][1,4]thiazinyl,    3′,4′-dihydrospiro[cyclobutane-1,2′-pyrido[3,2-b][1,4]oxazinyl,    3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl,    3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazinyl, imidazo[1,2-a]pyridinyl,    6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indolyl,    7,8,9,9a-tetrahydro-5H-pyrido[2,3-e]pyrrolo[1,2-a][1,4]diazepin-10(11H)-onyl,    indolyl, indolinyl, naphthyridinyl, pyrazolyl, pyridinyl, pyrazinyl,    pyrimidinyl, pyrrolyl, 1H-pyrrolo[2,3-b]pyridinyl, and thiazolyl,    each optionally substituted by one or more substituents    independently selected from the group consisting of oxo, alkyl,    halo, haloalkyl, cyano, N-heterocyclyl, N-heteroaryl, aryl,    —R⁸—OR^(6a), —R⁸—S(O)_(p)R^(6a) (where p is 0, 1 or 2),    —R⁸—C(O)R^(6a), —R⁸—C(O)OR^(6a), —R⁸—C(O)N(R^(6a))R^(7a),    —R⁸—N(R^(6a))R^(7a), —R⁸—N(R^(6a))—R⁹—N(R^(6a))R^(7a),    —R⁸—N(R^(6a))—R⁹—OR^(7a), —R⁸—N(R^(6a))C(O)R^(7a),    —R⁸—N(R^(6a))S(O)₂R^(7a), —R⁸—N(R^(6a))C(O)—R⁸—N(R^(6a))R^(7a), and    —R⁸—N(R^(6a))—R⁹—N(R^(6a))S(O)₂R^(7a), where the N-heterocyclyl, the    N-heteroaryl and the aryl are each independently optionally    substituted by one or more substituents selected from the group    consisting of —C(O)R⁶, —R⁸—N(R⁶)R⁷, —R⁸—C(O)N(R⁶)R⁷, alkyl, halo and    optionally substituted aryl;-   R^(5a) is selected from the group consisting of hydrogen, alkyl,    alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, optionally    substituted aryl, optionally substituted aralkyl, optionally    substituted aralkenyl, optionally substituted aralkynyl, optionally    substituted cycloalkyl, optionally substituted cycloalkylalkyl,    optionally substituted cycloalkylalkenyl, optionally substituted    cycloalkylalkynyl, optionally substituted heterocyclyl, optionally    substituted heterocyclylalkyl, optionally substituted    heterocyclylalkenyl, optionally substituted heterocyclylalkynyl,    optionally substituted heteroaryl, optionally substituted    heteroarylalkyl, optionally substituted heteroarylalkenyl,    optionally substituted heteroarylalkynyl, —R⁸—OR⁶, —R⁸—C(O)R⁶,    —R⁸—C(O)OR⁶, —R⁹—N(R⁶)R⁷, —R⁸—C(O)N(R⁶)R⁷, —R⁸—C(N═R⁶)N(R⁶)R⁷,    —R⁸—S(O)₂N(R⁶)R⁷, and —R⁸—S(O)_(t)R⁶ (where t is 1 or 2);-   each R⁶ and each R⁷ is independently selected from the group    consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl,    haloalkenyl, haloalkynyl, optionally substituted cycloalkyl,    optionally substituted cycloalkylalkyl, optionally substituted aryl,    optionally substituted aralkyl, optionally substituted aralkenyl,    optionally substituted aralkynyl, optionally substituted    heterocyclyl, optionally substituted heterocyclylalkyl, optionally    substituted heterocyclylalkenyl, optionally substituted    heterocyclylalkynyl, optionally substituted heteroaryl, optionally    substituted heteroarylalkyl, optionally substituted    heteroarylalkenyl, and optionally substituted heteroarylalkynyl; or    any R⁶ and R⁷, together with the common nitrogen to which they are    both attached, form an optionally substituted N-heteroaryl or an    optionally substituted N-heterocyclyl;-   R^(6a) and R^(7a) are each independently selected from the group    consisting of hydrogen, alkyl, optionally substituted cycloalkyl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, optionally substituted heteroaryl, and optionally    substituted aralkyl, and when any R^(6a) and R^(7a) are bonded to a    common nitrogen, R^(6a) and R^(7a) together with the common nitrogen    to which they are both attached, may form an optionally substituted    N-heteroaryl or an optionally substituted N-heterocyclyl; and-   each R⁸ is independently selected from the group consisting of a    direct bond and an optionally substituted straight or branched    alkylene chain; and-   each R⁹ is an optionally substituted straight or branched alkylene    chain.

Of this embodiment, one embodiment is a compound of formula (Ia-1c), asset forth above, wherein:

-   n is 0 or 1;-   R^(2a) is independently selected from the group consisting of    hydrogen, optionally substituted alkyl, halo, cyano and —OR⁶;-   R³, when present, is independently selected from the group    consisting of alkyl, halo and haloalkyl;-   R⁴ is pyridinyl substituted by one or more substituents selected    from the group consisting of alkyl, cyano, —R⁸—OR^(6a),    —R⁸—N(R^(6a))R^(7a), —R⁸—N(R^(6a))—R⁹—N(R^(6a))R^(7a) and    —R⁸—N(R^(6a))—R⁹—OR^(7a);-   R^(5a) is independently selected from the group consisting of    hydrogen, alkyl, —R⁸—C(O)R⁶ and —R⁸—S(O)_(t)R⁶ (where t is 1 or 2);-   R^(6a) and R^(7a) are each independently selected from the group    consisting of hydrogen, alkyl, optionally substituted cycloalkyl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, optionally substituted heteroaryl, and optionally    substituted aralkyl, and when any R^(6a) and R^(7a) are bonded to a    common nitrogen, R^(6a) and R^(7a) together with the common nitrogen    to which they are both attached, may form an optionally substituted    N-heteroaryl or an optionally substituted N-heterocyclyl;-   each R⁶ is independently selected from the group consisting of    hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl,    haloalkynyl, optionally substituted cycloalkyl, optionally    substituted cycloalkylalkyl, optionally substituted aryl, optionally    substituted aralkyl, optionally substituted aralkenyl, optionally    substituted aralkynyl, optionally substituted heterocyclyl,    optionally substituted heterocyclylalkyl, optionally substituted    heterocyclylalkenyl, optionally substituted heterocyclylalkynyl,    optionally substituted heteroaryl, optionally substituted    heteroarylalkyl, optionally substituted heteroarylalkenyl, and    optionally substituted heteroarylalkynyl;-   each R⁸ is independently selected from the group consisting of a    direct bond and an optionally substituted straight or branched    alkylene chain; and-   R⁹ is an optionally substituted straight or branched alkylene chain.

A specific embodiment of this embodiment is a compound of formula(Ia-1c), as set forth above, selected from the group consisting of:

-   4-(6-(dimethylamino)pyridin-3-yl)-N-(3-methyl-4-(1,5,7-trimethyl-3,7-diazabicyclo[3.3.1]nonan-3-yl)phenyl)pyrimidin-2-amine;-   4-(6-(cyclohexylamino)pyridin-3-yl)-N-(3-methyl-4-(1,5,7-trimethyl-3,7-diazabicyclo[3.3.1]nonan-3-yl)phenyl)pyrimidin-2-amine;-   4-(6-(dimethylamino)pyridin-3-yl)-N-(3-fluoro-4-(1,5,7-trimethyl-3,7-diazabicyclo[3.3.1]nonan-3-yl)phenyl)pyrimidin-2-amine;-   4-(4-(dimethylamino)phenyl)-N-(3-fluoro-4-(1,5,7-trimethyl-3,7-diazabicyclo[3.3.1]nonan-3-yl)phenyl)pyrimidin-2-amine;-   4-(6-(benzyl)pyridin-3-yl)-N-(3-methyl-4-(1,5,7-trimethyl-3,7-diazabicyclo[3.3.1]nonan-3-yl)phenyl)pyrimidin-2-amine;-   4-(6-(benzyl)pyridin-3-yl)-N-(3-fluoro-4-(1,5,7-trimethyl-3,7-diazabicyclo[3.3.1]nonan-3-yl)phenyl)pyrimidin-2-amine;-   4-(6-(3-ethoxypropyl)aminopyridin-3-yl)-N-(3-methyl-4-(1,5,7-trimethyl-3,7-diazabicyclo[3.3.1]nonan-3-yl)phenyl)pyrimidin-2-amine;-   4-(6-(propylamino)pyridin-3-yl)-N-(3-methyl-4-(1,5,7-trimethyl-3,7-diazabicyclo[3.3.1]nonan-3-yl)phenyl)pyrimidin-2-amine;-   4-(6-(3-dimethylamino)propylaminopyridin-3-yl)-N-(3-methyl-4-(1,5,7-trimethyl-3,7-diazabicyclo[3.3.1]nonan-3-yl)phenyl)pyrimidin-2-amine;    and-   4-(6-(2-methoxyethyl)(methyl)aminopyridin-3-yl)-N-(3-methyl-4-(1,5,7-trimethyl-3,7-diazabicyclo[3.3.1]nonan-3-yl)phenyl)pyrimidin-2-amine.

Another embodiment is a compound of formula (Ia-1c), as set forth above,wherein:

-   n is 0 or 1;-   R^(2a) is independently selected from the group consisting of    hydrogen, optionally substituted alkyl, halo, cyano and —OR⁶;-   R³, when present, is independently selected from the group    consisting of alkyl, halo and haloalkyl;-   R⁴ is pyridinyl substituted by an N-heterocyclyl selected from the    group consisting of morpholinyl, piperazinyl, piperidinyl,    oxazepanyl, 5-oxa-2-azabicyclo[2.2.1]heptanyl and thiamorpholinyl,    where the N-heterocyclyl is optionally substituted by one or more    substituents selected from the group consisting of —C(O)R⁶,    —R⁸—N(R⁶)R⁷, —R⁸—C(O)N(R⁶)R⁷, alkyl, halo and optionally substituted    aryl;-   R^(5a) is independently selected from the group consisting of    hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl,    optionally substituted cycloalkylalkyl, —R⁸—C(O)R⁶, —R⁸—C(O)N(R⁶)R⁷,    —R⁸—C(N═R⁶)N(R⁶)R⁷ and —R⁸—S(O)_(t)R⁶ (where t is 1 or 2);-   each R⁶ and each R⁷ is independently selected from the group    consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl,    haloalkenyl, haloalkynyl, optionally substituted cycloalkyl,    optionally substituted cycloalkylalkyl, optionally substituted aryl,    optionally substituted aralkyl, optionally substituted aralkenyl,    optionally substituted aralkynyl, optionally substituted    heterocyclyl, optionally substituted heterocyclylalkyl, optionally    substituted heterocyclylalkenyl, optionally substituted    heterocyclylalkynyl, optionally substituted heteroaryl, optionally    substituted heteroarylalkyl, optionally substituted    heteroarylalkenyl, and optionally substituted heteroarylalkynyl; or    any R⁶ and R⁷, together with the common nitrogen to which they are    both attached, form an optionally substituted N-heteroaryl or an    optionally substituted N-heterocyclyl;-   each R⁸ is independently selected from the group consisting of a    direct bond and an optionally substituted straight or branched    alkylene chain; and-   each R⁹ is an optionally substituted straight or branched alkylene    chain.

A specific embodiment of this embodiment is a compound of formula(Ia-1c), as set forth above, selected from the group consisting of:

-   4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-methyl-4-(1,5,7-trimethyl-3,7-diazabicyclo[3.3.1]nonan-3-yl)phenyl)pyrimidin-2-amine;-   4-(5-methyl-6-(morpholin-4-yl)pyridin-3-yl)-N-(3-fluoro-4-(1,5,7-trimethyl-3,7-diazabicyclo[3.3.1]nonan-3-yl)phenyl)pyrimidin-2-amine;-   4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-fluoro-4-(1,5,7-trimethyl-3,7-diazabicyclo[3.3.1]nonan-3-yl)phenyl)pyrimidin-2-amine;    and-   4-(6-((2S,6R)-2,6-dimethylmorpholin-4-yl)pyridin-3-yl)-N-(3-methyl-4-(1,5,7-trimethyl-3,7-diazabicyclo[3.3.1]nonan-3-yl)phenyl)pyrimidin-2-amine.

Another embodiment is a compound of formula (Ia-1c), as set forth above,wherein:

-   n is 0 or 1;-   R^(2a) is independently selected from the group consisting of    hydrogen, optionally substituted alkyl, halo, cyano and —OR⁶;-   R³, when present, is independently selected from the group    consisting of alkyl, halo and haloalkyl;-   R⁴ is selected from the group consisting of naphthyridinyl,    benzo[b]azepinyl, benzo[b][1,4]oxazinyl,    3,4-dihydro-2H-benzo[b][1,4]thiazinyl,    3′,4′-dihydrospiro[cyclobutane-1,2′-pyrido[3,2-b][1,4]oxazinyl,    3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazinyl and    3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl, each optionally    substituted by one or more substituents independently selected from    the group consisting of alkyl and oxo;-   R^(5a) is independently selected from the group consisting of    hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl,    optionally substituted cycloalkylalkyl, —R⁸—C(O)R⁶, —R⁸—C(O)N(R⁶)R⁷,    —R⁸—C(N═R⁶)N(R⁶)R⁷, —R⁸—S(O)_(t)R⁶ (where t is 1 or 2), and    —R⁸—S(O)₂N(R⁶)R⁷;-   each R⁶ and each R⁷ is independently selected from the group    consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl,    haloalkenyl, haloalkynyl, optionally substituted cycloalkyl,    optionally substituted cycloalkylalkyl, optionally substituted aryl,    optionally substituted aralkyl, optionally substituted aralkenyl,    optionally substituted aralkynyl, optionally substituted    heterocyclyl, optionally substituted heterocyclylalkyl, optionally    substituted heterocyclylalkenyl, optionally substituted    heterocyclylalkynyl, optionally substituted heteroaryl, optionally    substituted heteroarylalkyl, optionally substituted    heteroarylalkenyl, and optionally substituted heteroarylalkynyl; or    any R⁶ and R⁷, together with the common nitrogen to which they are    both attached, form an optionally substituted N-heteroaryl or an    optionally substituted N-heterocyclyl; and-   each R⁸ is independently selected from the group consisting of a    direct bond and an optionally substituted straight or branched    alkylene chain.

A specific embodiment of this embodiment is a compound of formula(Ia-1c), as set forth above, selected from the group consisting of:

-   4-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(3-methyl-4-(1,5,7-trimethyl-3,7-diazabicyclo[3.3.1]nonan-3-yl)phenyl)pyrimidin-2-amine;-   4-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(3-fluoro-4-(1,5,7-trimethyl-3,7-diazabicyclo[3.3.1]nonan-3-yl)phenyl)pyrimidin-2-amine;    and-   4-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(3-methyl-4-(1,5,7-trimethyl-3,7-diazabicyclo[3.3.1]nonan-3-yl)phenyl)pyrimidin-2-amine.

Another embodiment of the compounds of formula (Ia-1), as set forthabove, is a compound according to formula (Ia-1d):

wherein:

-   n is 0 or 1;-   R^(2a) is independently selected from the group consisting of    hydrogen, optionally substituted alkyl, halo, cyano and —OR⁶;-   R³, when present, is independently selected from the group    consisting of alkyl, halo and haloalkyl;-   R⁴ is selected from the group consisting of phenyl, benzimidazolyl,    benzo[b][1,4]oxazinyl, benzo[b]azepinyl,    2,3,4,5-tetrahydro-1H-benzo[b]azepinyl,    3,4-dihydro-2H-benzo[b][1,4]thiazinyl,    3′,4′-dihydrospiro[cyclobutane-1,2′-pyrido[3,2-b][1,4]oxazinyl,    3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl,    3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazinyl, imidazo[1,2-a]pyridinyl,    6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indolyl,    7,8,9,9a-tetrahydro-5H-pyrido[2,3-e]pyrrolo[1,2-a][1,4]diazepin-10(11H)-onyl,    indolyl, indolinyl, naphthyridinyl, pyrazolyl, pyridinyl, pyrazinyl,    pyrimidinyl, pyrrolyl, 1H-pyrrolo[2,3-b]pyridinyl, and thiazolyl,    each optionally substituted by one or more substituents    independently selected from the group consisting of oxo, alkyl,    halo, haloalkyl, cyano, N-heterocyclyl, N-heteroaryl, aryl,    —R⁸—OR^(6a), —R⁸—S(O)_(p)R^(6a) (where p is 0, 1 or 2),    —R⁸—C(O)R^(6a), —R⁸—C(O)OR^(6a), —R⁸—C(O)N(R^(6a))R^(7a),    —R⁸—N(R^(6a))R^(7a), —R⁸—N(R^(6a))—R⁹—N(R^(6a))R^(7a),    —R⁸—N(R^(6a))—R⁹—OR^(7a), —R⁸—N(R^(6a))C(O)R^(7a),    —R⁸—N(R^(6a))S(O)₂R^(7a), —R⁸—N(R^(6a))C(O)—R⁸—N(R^(6a))R^(7a), and    —R⁸—N(R^(6a))—R⁹—N(R^(6a))S(O)₂R^(7a), where the N-heterocyclyl, the    N-heteroaryl and the aryl are each independently optionally    substituted by one or more substituents selected from the group    consisting of —C(O)R⁶, —R⁸—N(R⁶)R⁷, —R⁸—C(O)N(R⁶)R⁷, alkyl, halo and    optionally substituted aryl;-   R^(5a) is independently selected from the group consisting of    hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl,    haloalkynyl, optionally substituted aryl, optionally substituted    aralkyl, optionally substituted aralkenyl, optionally substituted    aralkynyl, optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted cycloalkylalkenyl,    optionally substituted cycloalkylalkynyl, optionally substituted    heterocyclyl, optionally substituted heterocyclylalkyl, optionally    substituted heterocyclylalkenyl, optionally substituted    heterocyclylalkynyl, optionally substituted heteroaryl, optionally    substituted heteroarylalkyl, optionally substituted    heteroarylalkenyl, optionally substituted heteroarylalkynyl,    —R⁸—OR⁶, —R⁸—C(O)R⁶, —R⁸—C(O)OR⁶, —R⁹—N(R⁶)R⁷, —R⁸—C(O)N(R⁶)R⁷,    —R⁸—C(N═R⁶)N(R⁶)R⁷, —R⁸—S(O)₂N(R⁶)R⁷, and —R⁸—S(O)_(t)R⁶ (where t is    1 or 2);-   each R⁶ and each R⁷ is independently selected from the group    consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl,    haloalkenyl, haloalkynyl, optionally substituted cycloalkyl,    optionally substituted cycloalkylalkyl, optionally substituted aryl,    optionally substituted aralkyl, optionally substituted aralkenyl,    optionally substituted aralkynyl, optionally substituted    heterocyclyl, optionally substituted heterocyclylalkyl, optionally    substituted heterocyclylalkenyl, optionally substituted    heterocyclylalkynyl, optionally substituted heteroaryl, optionally    substituted heteroarylalkyl, optionally substituted    heteroarylalkenyl, and optionally substituted heteroarylalkynyl; or    any R⁶ and R⁷, together with the common nitrogen to which they are    both attached, form an optionally substituted N-heteroaryl or an    optionally substituted N-heterocyclyl;-   R^(6a) and R^(7a) are each independently selected from the group    consisting of hydrogen, alkyl, optionally substituted cycloalkyl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, optionally substituted heteroaryl, and optionally    substituted aralkyl, and when any R^(6a) and R^(7a) are bonded to a    common nitrogen, R^(6a) and R^(7a) together with the common nitrogen    to which they are both attached, may form an optionally substituted    N-heteroaryl or an optionally substituted N-heterocyclyl;-   each R⁹ is independently selected from the group consisting of a    direct bond and an optionally substituted straight or branched    alkylene chain; and-   each R⁹ is an optionally substituted straight or branched alkylene    chain.

Of this embodiment, one embodiment is a compound of formula (Ia-1d), asset forth above, wherein:

-   n is 0 or 1;-   R^(2a) is independently selected from the group consisting of    hydrogen, optionally substituted alkyl, halo, cyano and —OR⁶;-   R³, when present, is independently selected from the group    consisting of alkyl, halo and haloalkyl;-   R⁴ is pyridinyl substituted by one or more substituents selected    from the group consisting of alkyl, cyano, —R⁸—OR^(6a),    —R⁸—N(R^(6a))R^(7a), —R⁸—N(R^(6a))—R⁹—N(R^(6a))R^(7a) and    —R⁸—N(R^(6a))—R⁹—OR^(7a);-   R^(5a) is independently selected from the group consisting of    hydrogen, alkyl, —R⁸—C(O)R⁶ and —R⁸—S(O)_(t)R⁶ (where t is 1 or 2);-   each R⁶ is independently selected from the group consisting of    hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl,    haloalkynyl, optionally substituted cycloalkyl, optionally    substituted cycloalkylalkyl, optionally substituted aryl, optionally    substituted aralkyl, optionally substituted aralkenyl, optionally    substituted aralkynyl, optionally substituted heterocyclyl,    optionally substituted heterocyclylalkyl, optionally substituted    heterocyclylalkenyl, optionally substituted heterocyclylalkynyl,    optionally substituted heteroaryl, optionally substituted    heteroarylalkyl, optionally substituted heteroarylalkenyl, and    optionally substituted heteroarylalkynyl;-   R^(6a) and R^(7a) are each independently selected from the group    consisting of hydrogen, alkyl, optionally substituted cycloalkyl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, optionally substituted heteroaryl, and optionally    substituted aralkyl, and when any R^(6a) and R^(7a) are bonded to a    common nitrogen, R^(6a) and R^(7a) together with the common nitrogen    to which they are both attached, may form an optionally substituted    N-heteroaryl or an optionally substituted N-heterocyclyl;-   each R⁸ is independently selected from the group consisting of a    direct bond and an optionally substituted straight or branched    alkylene chain; and-   each R⁹ is an optionally substituted straight or branched alkylene    chain.

A specific embodiment of this embodiment is a compound of formula(Ia-1d), as set forth above, which is4-(6-aminopyridin-3-yl)-N-(4-(8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)pyrimidin-2-amine.

Another embodiment is a compound of formula (Ia-1d), as set forth above,wherein:

-   n is 0 or 1;-   R^(2a) is independently selected from the group consisting of    hydrogen, optionally substituted alkyl, halo, cyano and —OR⁶;-   R³, when present, is independently selected from the group    consisting of alkyl, halo and haloalkyl;-   R⁴ is pyridinyl substituted by an N-heterocyclyl selected from the    group consisting of morpholinyl, piperazinyl, piperidinyl,    oxazepanyl, 5-oxa-2-azabicyclo[2.2.1]heptanyl and thiamorpholinyl,    where the N-heterocyclyl is optionally substituted by one or more    substituents selected from the group consisting of —C(O)R⁶,    —R⁸—N(R⁶)R⁷, —R⁸—C(O)N(R⁶)R⁷, alkyl, halo and optionally substituted    aryl;-   R^(5a) is independently selected from the group consisting of    hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl,    optionally substituted cycloalkylalkyl, —R⁸—C(O)R⁶, —R⁸—C(O)N(R⁶)R⁷,    —R⁸—C(N═R⁶)N(R⁶)R⁷ and —R⁸—S(O)_(t)R⁶ (where t is 1 or 2);-   each R⁶ and each R⁷ is independently selected from the group    consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl,    haloalkenyl, haloalkynyl, optionally substituted cycloalkyl,    optionally substituted cycloalkylalkyl, optionally substituted aryl,    optionally substituted aralkyl, optionally substituted aralkenyl,    optionally substituted aralkynyl, optionally substituted    heterocyclyl, optionally substituted heterocyclylalkyl, optionally    substituted heterocyclylalkenyl, optionally substituted    heterocyclylalkynyl, optionally substituted heteroaryl, optionally    substituted heteroarylalkyl, optionally substituted    heteroarylalkenyl, and optionally substituted heteroarylalkynyl; or    any R⁶ and R⁷, together with the common nitrogen to which they are    both attached, form an optionally substituted N-heteroaryl or an    optionally substituted N-heterocyclyl; and-   each R⁸ is independently selected from the group consisting of a    direct bond and an optionally substituted straight or branched    alkylene chain.

A specific embodiment of this embodiment is a compound of formula(Ia-1d), as set forth above, selected from the group consisting of:

-   4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(4-(8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)pyrimidin-2-amine;    and-   4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-methyl-4-(8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)pyrimidin-2-amine.

Another embodiment is a compound of formula (Ia-1d), as set forth above,wherein:

-   n is 0 or 1;-   R^(2a) is independently selected from the group consisting of    hydrogen, optionally substituted alkyl, halo, cyano and —OR⁶;-   R³, when present, is independently selected from the group    consisting of alkyl, halo and haloalkyl;-   R⁴ is pyridinyl substituted by one or more substituents selected    from the group consisting of —R⁸—C(O)R^(6a),    —R⁸—C(O)N(R^(6a))R^(7a), —R⁸—S(O)_(p)R^(6a) (where p is 0, 1 or 2),    —R⁸—N(R^(6a))—R⁹—N(R^(6a))S(O)₂R^(7a), —R⁸—N(R^(6a))C(O)R^(7a),    —R⁸—N(R^(6a))S(O)₂R^(7a), —R⁸—N(R^(6a))C(O)—R⁸—N(R^(6a))R^(7a), and    tetrazolyl;-   R^(5a) is independently selected from the group consisting of    hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl,    optionally substituted cycloalkylalkyl, —R⁸—C(O)R⁶, —R⁸—C(O)N(R⁶)R⁷,    —R⁸—C(N═R⁶)N(R⁶)R⁷ and —R⁸—S(O)_(t)R⁶ (where t is 1 or 2);-   each R⁶ and each R⁷ is independently selected from the group    consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl,    haloalkenyl, haloalkynyl, optionally substituted cycloalkyl,    optionally substituted cycloalkylalkyl, optionally substituted aryl,    optionally substituted aralkyl, optionally substituted aralkenyl,    optionally substituted aralkynyl, optionally substituted    heterocyclyl, optionally substituted heterocyclylalkyl, optionally    substituted heterocyclylalkenyl, optionally substituted    heterocyclylalkynyl, optionally substituted heteroaryl, optionally    substituted heteroarylalkyl, optionally substituted    heteroarylalkenyl, and optionally substituted heteroarylalkynyl; or    any R⁶ and R⁷, together with the common nitrogen to which they are    both attached, form an optionally substituted N-heteroaryl or an    optionally substituted N-heterocyclyl;-   R^(6a) and R^(7a) are each independently selected from the group    consisting of hydrogen, alkyl, optionally substituted cycloalkyl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, optionally substituted heteroaryl, and optionally    substituted aralkyl, and when any R^(6a) and R^(7a) are bonded to a    common nitrogen, R^(6a) and R^(7a) together with the common nitrogen    to which they are both attached, may form an optionally substituted    N-heteroaryl or an optionally substituted N-heterocyclyl;-   each R⁸ is independently selected from the group consisting of a    direct bond and an optionally substituted straight or branched    alkylene chain; and-   R⁹ is an optionally substituted straight or branched alkylene chain.

A specific embodiment of this embodiment is a compound of formula(Ia-1d), as set forth above, selected from the group consisting of:

-   4-(6-(methylsulfonylamino)pyridin-3-yl)-N-(4-(8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)pyrimidin-2-amine;-   4-(4-(acetamido)phenyl)-N-(4-(8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)pyrimidin-2-amine;-   4-(6-(methylsulfonylamino)pyridin-3-yl)-N-(3-methyl-4-(8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)pyrimidin-2-amine;    and-   4-(4-(t-butylcarbonylamino)phenyl)-N-(3-methyl-4-(8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)pyrimidin-2-amine.

Another embodiment is a compound of formula (Ia-1d), as set forth above,wherein:

-   n is 0 or 1;-   R^(2a) is independently selected from the group consisting of    hydrogen, optionally substituted alkyl, halo, cyano and —OR⁶;-   R³, when present, is independently selected from the group    consisting of alkyl, halo and haloalkyl;-   R⁴ is selected from the group consisting of naphthyridinyl,    benzo[b]azepinyl, benzo[b][1,4]oxazinyl,    3,4-dihydro-2H-benzo[b][1,4]thiazinyl,    3′,4′-dihydrospiro[cyclobutane-1,2′-pyrido[3,2-b][1,4]oxazinyl,    3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazinyl and    3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl, each optionally    substituted by one or more substituents independently selected from    the group consisting of alkyl and oxo;-   R^(5a) is independently selected from the group consisting of    hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl,    optionally substituted cycloalkylalkyl, —R⁸—C(O)R⁶, —R⁸—C(O)N(R⁶)R⁷,    —R⁸—C(N═R⁶)N(R⁶)R⁷, —R⁸—S(O)_(t)R⁶ (where t is 1 or 2), and    —R⁸—S(O)₂N(R⁶)R⁷;-   each R⁶ and each R⁷ is independently selected from the group    consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl,    haloalkenyl, haloalkynyl, optionally substituted cycloalkyl,    optionally substituted cycloalkylalkyl, optionally substituted aryl,    optionally substituted aralkyl, optionally substituted aralkenyl,    optionally substituted aralkynyl, optionally substituted    heterocyclyl, optionally substituted heterocyclylalkyl, optionally    substituted heterocyclylalkenyl, optionally substituted    heterocyclylalkynyl, optionally substituted heteroaryl, optionally    substituted heteroarylalkyl, optionally substituted    heteroarylalkenyl, and optionally substituted heteroarylalkynyl; or    any R⁶ and R⁷, together with the common nitrogen to which they are    both attached, form an optionally substituted N-heteroaryl or an    optionally substituted N-heterocyclyl; and-   each R⁸ is independently selected from the group consisting of a    direct bond and an optionally substituted straight or branched    alkylene chain.

A specific embodiment of this embodiment is a compound of formula(Ia-1d), as set forth above, selected from the group consisting of:

-   4-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(4-(8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)pyrimidin-2-amine;    and-   4-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(3-methyl-4-(8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)pyrimidin-2-amine.

Another embodiment of the compounds of formula (Ia-1), as set forthabove, is a compound according to formula (Ia-1e):

wherein:

-   n is 0 or 1;-   R^(2a) is independently selected from the group consisting of    hydrogen, optionally substituted alkyl, halo, cyano and —OR⁶;-   R³, when present, is independently selected from the group    consisting of alkyl, halo and haloalkyl;-   R⁴ is selected from the group consisting of phenyl, benzimidazolyl,    benzo[b][1,4]oxazinyl, benzo[b]azepinyl,    2,3,4,5-tetrahydro-1H-benzo[b]azepinyl,    3,4-dihydro-2H-benzo[b][1,4]thiazinyl,    3′,4′-dihydrospiro[cyclobutane-1,2′-pyrido[3,2-b][1,4]oxazinyl,    3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl,    3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazinyl, imidazo[1,2-a]pyridinyl,    6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indolyl,    7,8,9,9a-tetrahydro-5H-pyrido[2,3-e]pyrrolo[1,2-a][1,4]diazepin-10(11H)-onyl,    indolyl, indolinyl, naphthyridinyl, pyrazolyl, pyridinyl, pyrazinyl,    pyrimidinyl, pyrrolyl, 1H-pyrrolo[2,3-b]pyridinyl, and thiazolyl,    each optionally substituted by one or more substituents    independently selected from the group consisting of oxo, alkyl,    halo, haloalkyl, cyano, N-heterocyclyl, N-heteroaryl, aryl,    —R⁸—OR^(6a), —R⁸—S(O)_(p)R^(6a) (where p is 0, 1 or 2),    —R⁸—C(O)R^(6a), —R⁸—C(O)OR^(6a), —R⁸—C(O)N(R^(6a))R^(7a),    —R⁸—N(R^(6a))R^(7a), —R⁸—N(R^(6a))—R⁹—N(R^(6a))R^(7a),    —R⁸—N(R^(6a))—R⁹—OR^(7a), —R⁸—N(R^(6a))C(O)R^(7a),    —R⁸—N(R^(6a))S(O)₂R^(7a), —R⁸—N(R^(6a))C(O)—R⁸—N(R^(6a))R^(7a), and    —R⁸—N(R^(6a)—R⁹—N(R^(6a))S(O)₂R^(7a), where the N-heterocyclyl, the    N-heteroaryl and the aryl are each independently optionally    substituted by one or more substituents selected from the group    consisting of —C(O)R⁶, —R⁸—N(R⁶)R⁷, —R⁸—C(O)N(R⁶)R⁷, alkyl, halo and    optionally substituted aryl;-   each R⁶ and each R⁷ is independently selected from the group    consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl,    haloalkenyl, haloalkynyl, optionally substituted cycloalkyl,    optionally substituted cycloalkylalkyl, optionally substituted aryl,    optionally substituted aralkyl, optionally substituted aralkenyl,    optionally substituted aralkynyl, optionally substituted    heterocyclyl, optionally substituted heterocyclylalkyl, optionally    substituted heterocyclylalkenyl, optionally substituted    heterocyclylalkynyl, optionally substituted heteroaryl, optionally    substituted heteroarylalkyl, optionally substituted    heteroarylalkenyl, and optionally substituted heteroarylalkynyl; or    any R⁶ and R⁷, together with the common nitrogen to which they are    both attached, form an optionally substituted N-heteroaryl or an    optionally substituted N-heterocyclyl;-   R^(6a) and R^(7a) are each independently selected from the group    consisting of hydrogen, alkyl, optionally substituted cycloalkyl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, optionally substituted heteroaryl, and optionally    substituted aralkyl, and when any R^(6a) and R^(7a) are bonded to a    common nitrogen, R^(6a) and R^(7a) together with the common nitrogen    to which they are both attached, may form an optionally substituted    N-heteroaryl or an optionally substituted N-heterocyclyl;-   each R⁸ is independently selected from the group consisting of a    direct bond and an optionally substituted straight or branched    alkylene chain; and-   each R⁹ is an optionally substituted straight or branched alkylene    chain.

Of this embodiment, one embodiment is a compound of formula (Ia-1e)wherein:

-   R⁴ is pyridinyl substituted by one or more substituents selected    from the group consisting of alkyl, cyano, —R⁸—OR^(6a),    —R⁸—N(R^(6a))R^(7a), —R⁸—N(R^(6a))—R⁹—N(R^(6a))R^(7a) and    —R⁸—N(R^(6a))—R⁹—OR^(7a); and-   R^(6a) and R^(7a) are each independently selected from the group    consisting of hydrogen, alkyl, optionally substituted cycloalkyl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, optionally substituted heteroaryl, and optionally    substituted aralkyl, and when any R^(6a) and R^(7a) are bonded to a    common nitrogen, R^(6a) and R^(7a) together with the common nitrogen    to which they are both attached, may form an optionally substituted    N-heteroaryl or an optionally substituted N-heterocyclyl.

A specific embodiment of this embodiment is a compound of formula(Ia-1e), as set forth above, which is4-(6-cyanopyridin-3-yl)-N-(3-methyl-4-(7-azabicyclo[2.2.1]heptan-7-yl)phenyl)pyrimidin-2-amine.

Another embodiment is a compound of formula (Ia-1e), as set forth above,wherein:

-   n is 0 or 1;-   R^(2a) is independently selected from the group consisting of    hydrogen, optionally substituted alkyl, halo, cyano and —OR⁶;-   R³, when present, is independently selected from the group    consisting of alkyl, halo and haloalkyl;-   R⁴ is pyridinyl substituted by an N-heterocyclyl selected from the    group consisting of morpholinyl, piperazinyl, piperidinyl,    oxazepanyl, 5-oxa-2-azabicyclo[2.2.1]heptanyl and thiamorpholinyl,    where the N-heterocyclyl is optionally substituted by one or more    substituents selected from the group consisting of —C(O)R⁶,    —R⁸—N(R⁶)R⁷, —R⁸—C(O)N(R⁶)R⁷, alkyl, halo and optionally substituted    aryl;-   each R⁶ and each R⁷ is independently selected from the group    consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl,    haloalkenyl, haloalkynyl, optionally substituted cycloalkyl,    optionally substituted cycloalkylalkyl, optionally substituted aryl,    optionally substituted aralkyl, optionally substituted aralkenyl,    optionally substituted aralkynyl, optionally substituted    heterocyclyl, optionally substituted heterocyclylalkyl, optionally    substituted heterocyclylalkenyl, optionally substituted    heterocyclylalkynyl, optionally substituted heteroaryl, optionally    substituted heteroarylalkyl, optionally substituted    heteroarylalkenyl, and optionally substituted heteroarylalkynyl; or    any R⁶ and R⁷, together with the common nitrogen to which they are    both attached, form an optionally substituted N-heteroaryl or an    optionally substituted N-heterocyclyl; and-   each R⁸ is independently selected from the group consisting of a    direct bond and an optionally substituted straight or branched    alkylene chain.

A specific embodiment of this embodiment is a compound of formula(Ia-1e), as set forth above, which is4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-methyl-4-(7-azabicyclo[2.2.1]heptan-7-yl)phenyl)pyrimidin-2-amine.

Another embodiment of the compounds of formula (Ia-1), as set forthabove, is a compound according to formula (Ia-1f):

wherein:

-   n is 0 or 1;-   R^(2a) is independently selected from the group consisting of    hydrogen, optionally substituted alkyl, halo, cyano and —OR⁶;-   R³, when present, is independently selected from the group    consisting of alkyl, halo and haloalkyl;-   R⁴ is selected from the group consisting of phenyl, benzimidazolyl,    benzo[b][1,4]oxazinyl, benzo[b]azepinyl,    2,3,4,5-tetrahydro-1H-benzo[b]azepinyl,    3,4-dihydro-2H-benzo[b][1,4]thiazinyl,    3′,4′-dihydrospiro[cyclobutane-1,2′-pyrido[3,2-b][1,4]oxazinyl,    3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl,    3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazinyl, imidazo[1,2-a]pyridinyl,    6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indolyl,    7,8,9,9a-tetrahydro-5H-pyrido[2,3-e]pyrrolo[1,2-a][1,4]diazepin-10(11H)-onyl,    indolyl, indolinyl, naphthyridinyl, pyrazolyl, pyridinyl, pyrazinyl,    pyrimidinyl, pyrrolyl, 1H-pyrrolo[2,3-b]pyridinyl, and thiazolyl,    each optionally substituted by one or more substituents    independently selected from the group consisting of oxo, alkyl,    halo, haloalkyl, cyano, N-heterocyclyl, N-heteroaryl, aryl,    —R⁸—OR^(6a), —R⁸—S(O)_(p)R^(6a) (where p is 0, 1 or 2),    —R⁸—C(O)R^(6a), —R⁸—C(O)OR^(6a), —R⁸—C(O)N(R^(6a))R^(7a),    —R⁸—N(R^(6a))R^(7a), —R⁸—N(R^(6a))—R⁹—N(R^(6a))R^(7a),    —R⁸—N(R^(6a))—R⁹—OR^(7a), —R⁸—N(R^(6a))C(O)R^(7a),    —R⁸—N(R^(6a))S(O)₂R^(7a), —R⁸—N(R^(6a))C(O)—R⁸—N(R^(6a))R^(7a), and    —R⁸—N(R^(6a))—R⁹—N(R^(6a))S(O)₂R^(7a), where the N-heterocyclyl, the    N-heteroaryl and the aryl are each independently optionally    substituted by one or more substituents selected from the group    consisting of —C(O)R⁶, —R⁸—N(R⁶)R⁷, —R⁸—C(O)N(R⁶)R⁷, alkyl, halo and    optionally substituted aryl;-   each R⁶ and each R⁷ is independently selected from the group    consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl,    haloalkenyl, haloalkynyl, optionally substituted cycloalkyl,    optionally substituted cycloalkylalkyl, optionally substituted aryl,    optionally substituted aralkyl, optionally substituted aralkenyl,    optionally substituted aralkynyl, optionally substituted    heterocyclyl, optionally substituted heterocyclylalkyl, optionally    substituted heterocyclylalkenyl, optionally substituted    heterocyclylalkynyl, optionally substituted heteroaryl, optionally    substituted heteroarylalkyl, optionally substituted    heteroarylalkenyl, and optionally substituted heteroarylalkynyl; or    any R⁶ and R⁷, together with the common nitrogen to which they are    both attached, form an optionally substituted N-heteroaryl or an    optionally substituted N-heterocyclyl;-   R^(6a) and R^(7a) are each independently selected from the group    consisting of hydrogen, alkyl, optionally substituted cycloalkyl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, optionally substituted heteroaryl, and optionally    substituted aralkyl, and when any R^(6a) and R^(7a) are bonded to a    common nitrogen, R^(6a) and R^(7a) together with the common nitrogen    to which they are both attached, may form an optionally substituted    N-heteroaryl or an optionally substituted N-heterocyclyl;-   each R⁸ is independently selected from the group consisting of a    direct bond and an optionally substituted straight or branched    alkylene chain; and-   each R⁹ is an optionally substituted straight or branched alkylene    chain.

Of this embodiment, one embodiment is a compound of formula (Ia-1f), asset forth above, wherein:

-   n is 0 or 1;-   R^(2a) is independently selected from the group consisting of    hydrogen, optionally substituted alkyl, halo, cyano and —OR⁶;-   R³, when present, is independently selected from the group    consisting of alkyl, halo and haloalkyl;-   R⁴ is pyridinyl substituted by —R⁸—OR^(6a);-   or R⁴ is pyridinyl substituted by an N-heterocyclyl selected from    the group consisting of morpholinyl, piperazinyl, piperidinyl,    oxazepanyl, 5-oxa-2-azabicyclo[2.2.1]heptanyl and thiamorpholinyl,    where the N-heterocyclyl is optionally substituted by —C(O)R⁶; and-   each R⁶ is independently selected from the group consisting of    hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl,    haloalkynyl, optionally substituted cycloalkyl, optionally    substituted cycloalkylalkyl, optionally substituted aryl, optionally    substituted aralkyl, optionally substituted aralkenyl, optionally    substituted aralkynyl, optionally substituted heterocyclyl,    optionally substituted heterocyclylalkyl, optionally substituted    heterocyclylalkenyl, optionally substituted heterocyclylalkynyl,    optionally substituted heteroaryl, optionally substituted    heteroarylalkyl, optionally substituted heteroarylalkenyl, and    optionally substituted heteroarylalkynyl; or any R⁶ and R⁷, together    with the common nitrogen to which they are both attached, form an    optionally substituted N-heteroaryl or an optionally substituted    N-heterocyclyl;-   R^(6a) is selected from the group consisting of hydrogen, alkyl,    optionally substituted cycloalkyl, optionally substituted    heterocyclyl, optionally substituted heterocyclylalkyl, optionally    substituted heteroaryl, and optionally substituted aralkyl; and-   R⁸ is independently selected from the group consisting of a direct    bond and an optionally substituted straight or branched alkylene    chain.

A specific embodiment of this embodiment is a compound of formula(Ia-1f), as set forth above, selected from the group consisting of:

-   4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-methyl-4-(1,4-diazabicyclo[3.2.1]octan-4-yl)phenyl)pyrimidin-2-amine;-   4-(6-(tetrahydropyran-4-yloxy)pyridin-3-yl)-N-(3-methyl-4-(1,4-diazabicyclo[3.2.1]octan-4-yl)phenyl)pyrimidin-2-amine;-   4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-methyl-4-((R)-1,4-diazabicyclo[3.2.1]octan-4-yl)phenyl)pyrimidin-2-amine;    and-   4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-methyl-4-((S)-1,4-diazabicyclo[3.2.1]octan-4-yl)phenyl)pyrimidin-2-amine.

Another embodiment is a compound of formula (Ia-1f), as set forth above,wherein:

-   n is 0 or 1;-   R^(2a) is independently selected from the group consisting of    hydrogen, optionally substituted alkyl, halo, cyano and —OR⁶;-   R³, when present, is independently selected from the group    consisting of alkyl, halo and haloalkyl;-   R⁴ is selected from the group consisting of benzimidazolyl,    imidazo[1,2-a]pyridinyl, indolyl, indolinyl, pyrazolyl, pyrazinyl,    pyrimidinyl, pyrrolyl, 1H-pyrrolo[2,3-b]pyridinyl,    3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl and thiazolyl, each    independently substituted by one or more substituents selected from    the group consisting of alkyl, cyano, oxo, —R⁸—OR^(6a),    —R⁸—N(R^(6a))R^(7a), —R⁸—C(O)N(R^(6a))R^(7a),    —R⁸—N(R^(6a))C(O)R^(7a), —R⁸—N(R^(6a))S(O)₂R^(7a),    —R⁸—N(R^(6a))C(O)—R⁸—N(R^(6a))R^(7a), aryl, N-heteroaryl and    N-heterocyclyl, where the aryl, the N-heterocyclyl and the    N-heteroaryl are each independently optionally substituted by one or    more substituents selected from the group consisting of —C(O)R⁶,    —R⁸—N(R⁶)R⁷, —R⁸—C(O)N(R⁶)R⁷, alkyl, halo and optionally substituted    aryl;-   R^(5a) is independently selected from the group consisting of    hydrogen, alkyl, —R⁸—C(O)R⁶ and —R⁸—S(O)_(t)R⁶ (where t is 1 or 2);-   each R⁶ and each R⁷ is independently selected from the group    consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl,    haloalkenyl, haloalkynyl, optionally substituted cycloalkyl,    optionally substituted cycloalkylalkyl, optionally substituted aryl,    optionally substituted aralkyl, optionally substituted aralkenyl,    optionally substituted aralkynyl, optionally substituted    heterocyclyl, optionally substituted heterocyclylalkyl, optionally    substituted heterocyclylalkenyl, optionally substituted    heterocyclylalkynyl, optionally substituted heteroaryl, optionally    substituted heteroarylalkyl, optionally substituted    heteroarylalkenyl, and optionally substituted heteroarylalkynyl; or    any R⁶ and R⁷, together with the common nitrogen to which they are    both attached, form an optionally substituted N-heteroaryl or an    optionally substituted N-heterocyclyl;-   R^(6a) and R^(7a) are each independently selected from the group    consisting of hydrogen, alkyl, optionally substituted cycloalkyl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, optionally substituted heteroaryl, and optionally    substituted aralkyl, and when any R^(6a) and R^(7a) are bonded to a    common nitrogen, R^(6a) and R^(7a) together with the common nitrogen    to which they are both attached, may form an optionally substituted    N-heteroaryl or an optionally substituted N-heterocyclyl; and-   each R⁸ is independently selected from the group consisting of a    direct bond and an optionally substituted straight or branched    alkylene chain.

A specific embodiment of this embodiment is a compound of formula(Ia-1f), as set forth above, selected from the group consisting of:

-   4-(2-oxoindolin-5-yl)-N-(3-methyl-4-(1,4-diazabicyclo[3.2.1]octan-4-yl)phenyl)pyrimidin-2-amine;-   (1-methylbenzimidazol-6-yl)-N-(3-methyl-4-(1,4-diazabicyclo[3.2.1]octan-4-yl)phenyl)pyrimidin-2-amine;-   4-(imidazo[1,2-a]pyridin-6-yl)-N-(3-methyl-4-(1,4-diazabicyclo[3.2.1]octan-4-yl)phenyl)pyrimidin-2-amine;    and-   4-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(3-methyl-4-(1,4-diazabicyclo[3.2.1]octan-4-yl)phenyl)pyrimidin-2-amine.

Another embodiment of the compounds of formula (Ia-1), as set forthabove, is a compound according to formula (Ia-1g):

wherein:

-   n is 0 or 1;-   R^(2a) is independently selected from the group consisting of    hydrogen, optionally substituted alkyl, halo, cyano and —OR⁶;-   R³, when present, is independently selected from the group    consisting of alkyl, halo and haloalkyl;-   R⁴ is selected from the group consisting of phenyl, benzimidazolyl,    benzo[b][1,4]oxazinyl, benzo[b]azepinyl,    2,3,4,5-tetrahydro-1H-benzo[b]azepinyl,    3,4-dihydro-2H-benzo[b][1,4]thiazinyl,    3′,4′-dihydrospiro[cyclobutane-1,2′-pyrido[3,2-b][1,4]oxazinyl,    3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl,    3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazinyl, imidazo[1,2-a]pyridinyl,    6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indolyl,    7,8,9,9a-tetrahydro-5H-pyrido[2,3-e]pyrrolo[1,2-a][1,4]diazepin-10(11H)-onyl,    indolyl, indolinyl, naphthyridinyl, pyrazolyl, pyridinyl, pyrazinyl,    pyrimidinyl, pyrrolyl, 1H-pyrrolo[2,3-b]pyridinyl, and thiazolyl,    each optionally substituted by one or more substituents    independently selected from the group consisting of oxo, alkyl,    halo, haloalkyl, cyano, N-heterocyclyl, N-heteroaryl, aryl,    —R⁸—OR^(6a), —R⁸—S(O)_(p)R^(6a) (where p is 0, 1 or 2),    —R⁸—C(O)R^(6a), —R⁸—C(O)OR^(6a), —R⁸—C(O)N(R^(6a))R^(7a),    —R⁸—N(R^(6a))R^(7a), —R⁸—N(R^(6a))—R⁹—N(R^(6a))R^(7a),    —R⁸—N(R^(6a))—R⁹—OR^(7a), —R⁸—N(R^(6a))C(O)R^(7a),    —R⁸—N(R^(6a))S(O)₂R^(7a), —R⁸—N(R^(6a))C(O)—R⁹—N(R^(6a))R^(7a), and    —R⁸—N(R^(6a))—R⁹—N(R^(6a))S(O)₂R^(7a), where the N-heterocyclyl, the    N-heteroaryl and the aryl are each independently optionally    substituted by one or more substituents selected from the group    consisting of —C(O)R⁶, —R⁸—N(R⁶)R⁷, —R⁸—C(O)N(R⁶)R⁷, alkyl, halo and    optionally substituted aryl;-   each R⁶ and each R⁷ is independently selected from the group    consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl,    haloalkenyl, haloalkynyl, optionally substituted cycloalkyl,    optionally substituted cycloalkylalkyl, optionally substituted aryl,    optionally substituted aralkyl, optionally substituted aralkenyl,    optionally substituted aralkynyl, optionally substituted    heterocyclyl, optionally substituted heterocyclylalkyl, optionally    substituted heterocyclylalkenyl, optionally substituted    heterocyclylalkynyl, optionally substituted heteroaryl, optionally    substituted heteroarylalkyl, optionally substituted    heteroarylalkenyl, and optionally substituted heteroarylalkynyl; or    any R⁶ and R⁷, together with the common nitrogen to which they are    both attached, form an optionally substituted N-heteroaryl or an    optionally substituted N-heterocyclyl;-   R^(6a) and R^(7a) are each independently selected from the group    consisting of hydrogen, alkyl, optionally substituted cycloalkyl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, optionally substituted heteroaryl, and optionally    substituted aralkyl, and when any R^(6a) and R^(7a) are bonded to a    common nitrogen, R^(6a) and R^(7a) together with the common nitrogen    to which they are both attached, may form an optionally substituted    N-heteroaryl or an optionally substituted N-heterocyclyl;-   each R⁸ is independently selected from the group consisting of a    direct bond and an optionally substituted straight or branched    alkylene chain; and-   each R⁹ is an optionally substituted straight or branched alkylene    chain.

In one embodiment the compound has formula (Ia-1g), as set forth above,wherein:

-   n is 0 or 1;-   R^(2a) is independently selected from the group consisting of    hydrogen, optionally substituted alkyl, halo, cyano and —OR⁶;-   R³, when present, is independently selected from the group    consisting of alkyl, halo and haloalkyl;-   R⁴ is pyridinyl substituted by an N-heterocyclyl selected from the    group consisting of morpholinyl, piperazinyl, piperidinyl,    oxazepanyl, 5-oxa-2-azabicyclo[2.2.1]heptanyl and thiamorpholinyl,    where the N-heterocyclyl is optionally substituted by one or more    substituents selected from the group consisting of —C(O)R⁶,    —R⁸—N(R⁶)R⁷, —R⁸—C(O)N(R⁶)R⁷, alkyl, halo and optionally substituted    aryl;-   each R⁶ and each R⁷ is independently selected from the group    consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl,    haloalkenyl, haloalkynyl, optionally substituted cycloalkyl,    optionally substituted cycloalkylalkyl, optionally substituted aryl,    optionally substituted aralkyl, optionally substituted aralkenyl,    optionally substituted aralkynyl, optionally substituted    heterocyclyl, optionally substituted heterocyclylalkyl, optionally    substituted heterocyclylalkenyl, optionally substituted    heterocyclylalkynyl, optionally substituted heteroaryl, optionally    substituted heteroarylalkyl, optionally substituted    heteroarylalkenyl, and optionally substituted heteroarylalkynyl; or    any R⁶ and R⁷, together with the common nitrogen to which they are    both attached, form an optionally substituted N-heteroaryl or an    optionally substituted N-heterocyclyl; and-   each R⁹ is independently selected from the group consisting of a    direct bond and an optionally substituted straight or branched    alkylene chain.

A specific embodiment of this embodiment is a compound of formula(Ia-1g), as set forth above, selected from the group consisting of:

-   4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-methyl-4-(1,4-diazabicyclo[3.2.2]nonan-4-yl)phenyl)pyrimidin-2-amine;    and-   4-(6-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)pyridin-3-yl)-N-(3-methyl-4-(1,4-diazabicyclo[3.2.2]nonan-4-yl)phenyl)pyrimidin-2-amine.

Another embodiment is a compound of formula (Ia-1g), as set forth above,wherein:

-   n is 0 or 1;-   R^(2a) is independently selected from the group consisting of    hydrogen, optionally substituted alkyl, halo, cyano and —OR⁶;-   R³, when present, is independently selected from the group    consisting of alkyl, halo and haloalkyl;-   R⁴ is pyridinyl substituted by one or more substituents selected    from the group consisting of —R⁸—C(O)R^(6a),    —R⁸—C(O)N(R^(6a))R^(7a), —R⁸—S(O)_(p)R^(6a) (where p is 0, 1 or 2),    —R⁸—N(R^(6a))—R⁹—N(R^(6a))S(O)₂R^(7a), —R⁸—N(R^(6a))C(O)R^(7a),    —R⁸—N(R^(6a))S(O)₂R^(7a), —R⁸—N(R^(6a))C(O)—R⁸—N(R^(6a))R^(7a), and    tetrazolyl;-   R⁶ is selected from the group consisting of hydrogen, alkyl,    alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, optionally    substituted cycloalkyl, optionally substituted cycloalkylalkyl,    optionally substituted aryl, optionally substituted aralkyl,    optionally substituted aralkenyl, optionally substituted aralkynyl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, optionally substituted heterocyclylalkenyl,    optionally substituted heterocyclylalkynyl, optionally substituted    heteroaryl, optionally substituted heteroarylalkyl, optionally    substituted heteroarylalkenyl, and optionally substituted    heteroarylalkynyl;-   R^(6a) and R^(7a) are each independently selected from the group    consisting of hydrogen, alkyl, optionally substituted cycloalkyl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, optionally substituted heteroaryl, and optionally    substituted aralkyl, and when any R^(6a) and R^(7a) are bonded to a    common nitrogen, R^(6a) and R^(7a) together with the common nitrogen    to which they are both attached, may form an optionally substituted    N-heteroaryl or an optionally substituted N-heterocyclyl;-   each R⁸ is independently selected from the group consisting of a    direct bond and an optionally substituted straight or branched    alkylene chain; and-   R⁹ is an optionally substituted straight or branched alkylene chain.

A specific embodiment of this embodiment is a compound of formula(Ia-1g), as set forth above, which is4-(4-((pyridin-2-yl)aminocarbonyl)phenyl)-N-(3-methyl-4-(1,4-diazabicyclo[3.2.2]nonan-4-yl)phenyl)pyrimidin-2-amine.

Another embodiment is a compound of formula (Ia-1g), as set forth above,wherein:

-   n is 0 or 1;-   R^(2a) is independently selected from the group consisting of    hydrogen, optionally substituted alkyl, halo, cyano and —OR⁶;-   R³, when present, is independently selected from the group    consisting of alkyl, halo and haloalkyl;-   R⁴ is selected from the group consisting of naphthyridinyl,    benzo[b]azepinyl, benzo[b][1,4]oxazinyl,    3,4-dihydro-2H-benzo[b][1,4]thiazinyl,    3′,4′-dihydrospiro[cyclobutane-1,2′-pyrido[3,2-b][1,4]oxazinyl,    3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazinyl and    3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl, each optionally    substituted by one or more substituents independently selected from    the group consisting of alkyl and oxo; and-   R⁶ is selected from the group consisting of hydrogen, alkyl,    alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, optionally    substituted cycloalkyl, optionally substituted cycloalkylalkyl,    optionally substituted aryl, optionally substituted aralkyl,    optionally substituted aralkenyl, optionally substituted aralkynyl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, optionally substituted heterocyclylalkenyl,    optionally substituted heterocyclylalkynyl, optionally substituted    heteroaryl, optionally substituted heteroarylalkyl, optionally    substituted heteroarylalkenyl, and optionally substituted    heteroarylalkynyl.

A specific embodiment of this embodiment is a compound of formula(Ia-1g), as set forth above, which is4-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(3-methyl-4-(1,4-diazabicyclo[3.2.2]nonan-4-yl)phenyl)pyrimidin-2-amine.

Another embodiment of the compounds of formula (Ia-1), as set forthabove, is a compound according to formula (Ia-1h):

wherein:

-   n is 0 or 1;-   R^(2a) is independently selected from the group consisting of    hydrogen, optionally substituted alkyl, halo, cyano and —OR⁶;-   R³, when present, is independently selected from the group    consisting of alkyl, halo and haloalkyl;-   R⁴ is selected from the group consisting of phenyl, benzimidazolyl,    benzo[b][1,4]oxazinyl, benzo[b]azepinyl,    2,3,4,5-tetrahydro-1H-benzo[b]azepinyl,    3,4-dihydro-2H-benzo[b][1,4]thiazinyl,    3′,4′-dihydrospiro[cyclobutane-1,2′-pyrido[3,2-b][1,4]oxazinyl,    3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl,    3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazinyl, imidazo[1,2-a]pyridinyl,    6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indolyl,    7,8,9,9a-tetrahydro-5H-pyrido[2,3-e]pyrrolo[1,2-a][1,4]diazepin-10(11H)-onyl,    indolyl, indolinyl, naphthyridinyl, pyrazolyl, pyridinyl, pyrazinyl,    pyrimidinyl, pyrrolyl, 1H-pyrrolo[2,3-b]pyridinyl, and thiazolyl,    each optionally substituted by one or more substituents    independently selected from the group consisting of oxo, alkyl,    halo, haloalkyl, cyano, N-heterocyclyl, N-heteroaryl, aryl,    —R⁸—OR^(6a), —R⁸—S(O)_(p)R^(6a) (where p is 0, 1 or 2),    —R⁸—C(O)R^(6a), —R⁸—C(O)OR^(6a), —R⁸—C(O)N(R^(6a))R^(7a),    —R⁸—N(R^(6a))R^(7a), —R⁸—N(R^(6a))—R⁹—N(R^(6a))R^(7a),    —R⁸—N(R^(6a))—R⁹—OR^(7a), —R⁸—N(R^(6a))C(O)R^(7a),    —R⁸—N(R^(6a))S(O)₂R^(7a), —R⁸—N(R^(6a))C(O)—R⁸—N(R^(6a))R^(7a), and    —R⁸—N(R^(6a))—R⁹—N(R^(6a))S(O)₂R^(7a), where the N-heterocyclyl, the    N-heteroaryl and the aryl are each independently optionally    substituted by one or more substituents selected from the group    consisting of —C(O)R⁶, —R⁸—N(R⁶)R⁷, —R⁸—C(O)N(R⁶)R⁷, alkyl, halo and    optionally substituted aryl;-   each R⁶ and each R⁷ is independently selected from the group    consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl,    haloalkenyl, haloalkynyl, optionally substituted cycloalkyl,    optionally substituted cycloalkylalkyl, optionally substituted aryl,    optionally substituted aralkyl, optionally substituted aralkenyl,    optionally substituted aralkynyl, optionally substituted    heterocyclyl, optionally substituted heterocyclylalkyl, optionally    substituted heterocyclylalkenyl, optionally substituted    heterocyclylalkynyl, optionally substituted heteroaryl, optionally    substituted heteroarylalkyl, optionally substituted    heteroarylalkenyl, and optionally substituted heteroarylalkynyl; or    any R⁶ and R⁷, together with the common nitrogen to which they are    both attached, form an optionally substituted N-heteroaryl or an    optionally substituted N-heterocyclyl;-   R^(6a) and R^(7a) are each independently selected from the group    consisting of hydrogen, alkyl, optionally substituted cycloalkyl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, optionally substituted heteroaryl, and optionally    substituted aralkyl, and when any R^(6a) and R^(7a) are bonded to a    common nitrogen, R^(6a) and R^(7a) together with the common nitrogen    to which they are both attached, may form an optionally substituted    N-heteroaryl or an optionally substituted N-heterocyclyl;-   each R⁸ is independently selected from the group consisting of a    direct bond and an optionally substituted straight or branched    alkylene chain; and-   each R⁹ is an optionally substituted straight or branched alkylene    chain.

In one embodiment the compound has formula (Ia-1h), as set forth above,wherein:

-   n is 0 or 1;-   R^(2a) is independently selected from the group consisting of    hydrogen, optionally substituted alkyl, halo, cyano and —OR⁶;-   R³, when present, is independently selected from the group    consisting of alkyl, halo and haloalkyl;-   R⁴ is pyridinyl substituted by an N-heterocyclyl selected from the    group consisting of morpholinyl, piperazinyl, piperidinyl,    oxazepanyl, 5-oxa-2-azabicyclo[2.2.1]heptanyl and thiamorpholinyl,    where the N-heterocyclyl is optionally substituted by one or more    substituents selected from the group consisting of —C(O)R⁶,    —R⁸—N(R⁶)R⁷, —R⁸—C(O)N(R⁶)R⁷, alkyl, halo and optionally substituted    aryl;-   each R⁶ and each R⁷ is independently selected from the group    consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl,    haloalkenyl, haloalkynyl, optionally substituted cycloalkyl,    optionally substituted cycloalkylalkyl, optionally substituted aryl,    optionally substituted aralkyl, optionally substituted aralkenyl,    optionally substituted aralkynyl, optionally substituted    heterocyclyl, optionally substituted heterocyclylalkyl, optionally    substituted heterocyclylalkenyl, optionally substituted    heterocyclylalkynyl, optionally substituted heteroaryl, optionally    substituted heteroarylalkyl, optionally substituted    heteroarylalkenyl, and optionally substituted heteroarylalkynyl; or    any R⁶ and R⁷, together with the common nitrogen to which they are    both attached, form an optionally substituted N-heteroaryl or an    optionally substituted N-heterocyclyl; and-   each R⁸ is independently selected from the group consisting of a    direct bond and an optionally substituted straight or branched    alkylene chain.

A specific embodiment of this embodiment is a compound of formula(Ia-1h), as set forth above, which is4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-methyl-4-((1S,4R)-2-azabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine.

Another embodiment is a compound of formula (Ia-1h), as set forth above,wherein:

-   n is 0 or 1;-   R^(2a) is independently selected from the group consisting of    hydrogen, optionally substituted alkyl, halo, cyano and —OR⁶;-   R³, when present, is independently selected from the group    consisting of alkyl, halo and haloalkyl;-   R⁴ is selected from the group consisting of naphthyridinyl,    benzo[b]azepinyl, benzo[b][1,4]oxazinyl,    3,4-dihydro-2H-benzo[b][1,4]thiazinyl,    3′,4′-dihydrospiro[cyclobutane-1,2′-pyrido[3,2-b][1,4]oxazinyl,    3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazinyl and    3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl, each optionally    substituted by one or more substituents independently selected from    the group consisting of alkyl and oxo; and-   R⁶ is selected from the group consisting of hydrogen, alkyl,    alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, optionally    substituted cycloalkyl, optionally substituted cycloalkylalkyl,    optionally substituted aryl, optionally substituted aralkyl,    optionally substituted aralkenyl, optionally substituted aralkynyl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, optionally substituted heterocyclylalkenyl,    optionally substituted heterocyclylalkynyl, optionally substituted    heteroaryl, optionally substituted heteroarylalkyl, optionally    substituted heteroarylalkenyl, and optionally substituted    heteroarylalkynyl.

A specific embodiment of this embodiment is a compound of formula(Ia-1h) which is4-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(3-methyl-4-((1S,4R)-2-azabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine.

Another embodiment of the compounds of formula (Ia-1), as set forthabove, is a compound according to formula (Ia-1i):

wherein:

-   n is 0 or 1;-   R^(2a) is independently selected from the group consisting of    hydrogen, optionally substituted alkyl, halo, cyano and —OR⁶;-   R³, when present, is independently selected from the group    consisting of alkyl, halo and haloalkyl;-   R⁴ is selected from the group consisting of phenyl, benzimidazolyl,    benzo[b][1,4]oxazinyl, benzo[b]azepinyl,    2,3,4,5-tetrahydro-1H-benzo[b]azepinyl,    3,4-dihydro-2H-benzo[b][1,4]thiazinyl,    3′,4′-dihydrospiro[cyclobutane-1,2′-pyrido[3,2-b][1,4]oxazinyl,    3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl,    3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazinyl, imidazo[1,2-a]pyridinyl,    6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indolyl,    7,8,9,9a-tetrahydro-5H-pyrido[2,3-e]pyrrolo[1,2-a][1,4]diazepin-10(11H)-onyl,    indolyl, indolinyl, naphthyridinyl, pyrazolyl, pyridinyl, pyrazinyl,    pyrimidinyl, pyrrolyl, 1H-pyrrolo[2,3-b]pyridinyl, and thiazolyl,    each optionally substituted by one or more substituents    independently selected from the group consisting of oxo, alkyl,    halo, haloalkyl, cyano, N-heterocyclyl, N-heteroaryl, aryl,    —R⁸—OR^(6a), —R⁸—S(O)_(p)R^(6a) (where p is 0, 1 or 2),    —R⁸—C(O)R^(6a), —R⁸—C(O)OR^(6a), —R⁸—C(O)N(R^(6a))R^(7a),    —R⁸—N(R^(6a))R^(7a), —R⁸—N(R^(6a))—R⁹—N(R^(6a))R^(7a),    —R⁸—N(R^(6a))—R⁹—OR^(7a), —R⁸—N(R^(6a))C(O)R^(7a),    —R⁸—N(R^(6a))S(O)₂R^(7a), —R⁸—N(R^(6a))C(O)—R⁸—N(R^(6a))R^(7a), and    —R⁸—N(R^(6a))—R⁹—N(R^(6a))S(O)₂R^(7a), where the N-heterocyclyl, the    N-heteroaryl and the aryl are each independently optionally    substituted by one or more substituents selected from the group    consisting of —C(O)R⁶, —R⁸—N(R⁶)R⁷, —R⁸—C(O)N(R⁶)R⁷, alkyl, halo and    optionally substituted aryl;-   R^(5a) is selected from the group consisting of hydrogen, alkyl,    alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, optionally    substituted aryl, optionally substituted aralkyl, optionally    substituted aralkenyl, optionally substituted aralkynyl, optionally    substituted cycloalkyl, optionally substituted cycloalkylalkyl,    optionally substituted cycloalkylalkenyl, optionally substituted    cycloalkylalkynyl, optionally substituted heterocyclyl, optionally    substituted heterocyclylalkyl, optionally substituted    heterocyclylalkenyl, optionally substituted heterocyclylalkynyl,    optionally substituted heteroaryl, optionally substituted    heteroarylalkyl, optionally substituted heteroarylalkenyl,    optionally substituted heteroarylalkynyl, —R⁸—OR⁶, —R⁸—C(O)R⁶,    —R⁸—C(O)OR⁶, —R⁹—N(R⁶)R⁷, —R⁸—C(O)N(R⁶)R⁷, —R⁸—C(N═R⁶)N(R⁶)R⁷,    —R⁸—S(O)₂N(R⁶)R⁷, and —R⁸—S(O)_(t)R⁶ (where t is 1 or 2);-   each R⁶ and each R⁷ is independently selected from the group    consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl,    haloalkenyl, haloalkynyl, optionally substituted cycloalkyl,    optionally substituted cycloalkylalkyl, optionally substituted aryl,    optionally substituted aralkyl, optionally substituted aralkenyl,    optionally substituted aralkynyl, optionally substituted    heterocyclyl, optionally substituted heterocyclylalkyl, optionally    substituted heterocyclylalkenyl, optionally substituted    heterocyclylalkynyl, optionally substituted heteroaryl, optionally    substituted heteroarylalkyl, optionally substituted    heteroarylalkenyl, and optionally substituted heteroarylalkynyl; or    any R⁶ and R⁷, together with the common nitrogen to which they are    both attached, form an optionally substituted N-heteroaryl or an    optionally substituted N-heterocyclyl;-   R^(6a) and R^(7a) are each independently selected from the group    consisting of hydrogen, alkyl, optionally substituted cycloalkyl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, optionally substituted heteroaryl, and optionally    substituted aralkyl, and when any R^(6a) and R^(7a) are bonded to a    common nitrogen, R^(6a) and R^(7a) together with the common nitrogen    to which they are both attached, may form an optionally substituted    N-heteroaryl or an optionally substituted N-heterocyclyl;-   each R⁸ is independently selected from the group consisting of a    direct bond and an optionally substituted straight or branched    alkylene chain; and-   each R⁹ is an optionally substituted straight or branched alkylene    chain.

Of this embodiment, one embodiment is a compound of formula (Ia-1i), asset forth above, wherein:

-   n is 0 or 1;-   R^(2a) is independently selected from the group consisting of    hydrogen, optionally substituted alkyl, halo, cyano and —OR⁶;-   R³, when present, is independently selected from the group    consisting of alkyl, halo and haloalkyl;-   R⁴ is pyridinyl substituted by an N-heterocyclyl selected from the    group consisting of morpholinyl, piperazinyl, piperidinyl,    oxazepanyl, 5-oxa-2-azabicyclo[2.2.1]heptanyl and thiamorpholinyl,    where the N-heterocyclyl is optionally substituted by one or more    substituents selected from the group consisting of —C(O)R⁶,    —R⁸—N(R⁶)R⁷, —R⁸—C(O)N(R⁶)R⁷, alkyl, halo and optionally substituted    aryl;-   R^(5a) is independently selected from the group consisting of    hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl,    optionally substituted cycloalkylalkyl, —R⁸—C(O)R⁶, —R⁸—C(O)N(R⁶)R⁷,    —R⁸—C(N═R⁶)N(R⁶)R⁷ and —R⁸—S(O)_(t)R⁶ (where t is 1 or 2);-   each R⁶ and each R⁷ is independently selected from the group    consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl,    haloalkenyl, haloalkynyl, optionally substituted cycloalkyl,    optionally substituted cycloalkylalkyl, optionally substituted aryl,    optionally substituted aralkyl, optionally substituted aralkenyl,    optionally substituted aralkynyl, optionally substituted    heterocyclyl, optionally substituted heterocyclylalkyl, optionally    substituted heterocyclylalkenyl, optionally substituted    heterocyclylalkynyl, optionally substituted heteroaryl, optionally    substituted heteroarylalkyl, optionally substituted    heteroarylalkenyl, and optionally substituted heteroarylalkynyl; or    any R⁶ and R⁷, together with the common nitrogen to which they are    both attached, form an optionally substituted N-heteroaryl or an    optionally substituted N-heterocyclyl; and-   each R⁸ is independently selected from the group consisting of a    direct bond and an optionally substituted straight or branched    alkylene chain.

A specific embodiment of this embodiment is a compound of formula(Ia-1i), as set forth above, selected from the group consisting of:

-   4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-methyl-4-(2-methylsulfonyl-2-azabicyclo[2.2.1]heptan-5-yl)phenyl)pyrimidin-2-amine;-   4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-methyl-4-(2-methylsulfonyl-2-azabicyclo[2.2.1]heptan-6-yl)phenyl)pyrimidin-2-amine;-   4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(4-(2-methylsulfonyl-2-azabicyclo[2.2.1]heptan-5-yl)phenyl)pyrimidin-2-amine;    and-   4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(4-(2-methylsulfonyl-2-azabicyclo[2.2.1]heptan-6-yl)phenyl)pyrimidin-2-amine.

Another embodiment is a compound of formula (Ia-1i), as set forth above,wherein:

-   n is 0 or 1;-   R^(2a) is independently selected from the group consisting of    hydrogen, optionally substituted alkyl, halo, cyano and —OR⁶;-   R³, when present, is independently selected from the group    consisting of alkyl, halo and haloalkyl;-   R⁴ is selected from the group consisting of naphthyridinyl,    benzo[b]azepinyl, benzo[b][1,4]oxazinyl,    3,4-dihydro-2H-benzo[b][1,4]thiazinyl,    3′,4′-dihydrospiro[cyclobutane-1,2′-pyrido[3,2-b][1,4]oxazinyl,    3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazinyl and    3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl, each optionally    substituted by one or more substituents independently selected from    the group consisting of alkyl and oxo;-   R^(5a) is independently selected from the group consisting of    hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl,    optionally substituted cycloalkylalkyl, —R⁸—C(O)R⁶, —R⁸—C(O)N(R⁶)R⁷,    —R⁸—C(N═R⁶)N(R⁶)R⁷, —R⁸—S(O)_(t)R⁶ (where t is 1 or 2), and    —R⁸—S(O)₂N(R⁶)R⁷;-   each R⁶ and each R⁷ is independently selected from the group    consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl,    haloalkenyl, haloalkynyl, optionally substituted cycloalkyl,    optionally substituted cycloalkylalkyl, optionally substituted aryl,    optionally substituted aralkyl, optionally substituted aralkenyl,    optionally substituted aralkynyl, optionally substituted    heterocyclyl, optionally substituted heterocyclylalkyl, optionally    substituted heterocyclylalkenyl, optionally substituted    heterocyclylalkynyl, optionally substituted heteroaryl, optionally    substituted heteroarylalkyl, optionally substituted    heteroarylalkenyl, and optionally substituted heteroarylalkynyl; or    any R⁶ and R⁷, together with the common nitrogen to which they are    both attached, form an optionally substituted N-heteroaryl or an    optionally substituted N-heterocyclyl; and-   each R⁸ is independently selected from the group consisting of a    direct bond and an optionally substituted straight or branched    alkylene chain.

A specific embodiment of this embodiment is a compound of formula(Ia-1i), as set forth above, selected from the group consisting of:

-   4-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(3-methyl-4-(2-methylsulfonyl-2-azabicyclo[2.2.1]heptan-5-yl)phenyl)pyrimidin-2-amine;-   4-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(3-methyl-4-(2-methylsulfonyl-2-azabicyclo[2.2.1]heptan-6-yl)phenyl)pyrimidin-2-amine;-   4-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(4-(2-methylsulfonyl-2-azabicyclo[2.2.1]heptan-5-yl)phenyl)pyrimidin-2-amine;    and-   4-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(4-(2-methylsulfonyl-2-azabicyclo[2.2.1]heptan-6-yl)phenyl)pyrimidin-2-amine.

Another embodiment of the compounds of formula (Ia-1), as set forthabove, is a compound according to formula (Ia-1j):

wherein n is 0 or 1;

-   R^(2a) is independently selected from the group consisting of    hydrogen, optionally substituted alkyl, halo, cyano and —OR⁶;-   R³, when present, is independently selected from the group    consisting of alkyl, halo and haloalkyl;-   R⁴ is selected from the group consisting of phenyl, benzimidazolyl,    benzo[b][1,4]oxazinyl, benzo[b]azepinyl,    2,3,4,5-tetrahydro-1H-benzo[b]azepinyl,    3,4-dihydro-2H-benzo[b][1,4]thiazinyl,    3′,4′-dihydrospiro[cyclobutane-1,2′-pyrido[3,2-b][1,4]oxazinyl,    3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl,    3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazinyl, imidazo[1,2-a]pyridinyl,    6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indolyl,    7,8,9,9a-tetrahydro-5H-pyrido[2,3-e]pyrrolo[1,2-a][1,4]diazepin-10(11H)-onyl,    indolyl, indolinyl, naphthyridinyl, pyrazolyl, pyridinyl, pyrazinyl,    pyrimidinyl, pyrrolyl, 1H-pyrrolo[2,3-b]pyridinyl, and thiazolyl,    each optionally substituted by one or more substituents    independently selected from the group consisting of oxo, alkyl,    halo, haloalkyl, cyano, N-heterocyclyl, N-heteroaryl, aryl,    —R⁸—OR^(6a), —R⁸—S(O)_(p)R^(6a) (where p is 0, 1 or 2),    —R⁸—C(O)R^(6a), —R⁸—C(O)OR^(6a), —R⁸—C(O)N(R^(6a))R^(7a),    —R⁸—N(R^(6a))R^(7a), —R⁸—N(R^(6a))—R⁹—N(R^(6a))R^(7a),    —R⁸—N(R^(6a))—R⁹—OR^(7a), —R⁸—N(R^(6a))C(O)R^(7a),    —R⁸—N(R^(6a))S(O)₂R^(7a), —R⁸—N(R^(6a))C(O)—R⁸—N(R^(6a))R^(7a), and    —R⁸—N(R^(6a)—R⁹—N(R^(6a))S(O)₂R^(7a), where the N-heterocyclyl, the    N-heteroaryl and the aryl are each independently optionally    substituted by one or more substituents selected from the group    consisting of —C(O)R⁶, —R⁸—N(R⁶)R⁷, —R⁸—C(O)N(R⁶)R⁷, alkyl, halo and    optionally substituted aryl;-   each R⁶ and each R⁷ is independently selected from the group    consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl,    haloalkenyl, haloalkynyl, optionally substituted cycloalkyl,    optionally substituted cycloalkylalkyl, optionally substituted aryl,    optionally substituted aralkyl, optionally substituted aralkenyl,    optionally substituted aralkynyl, optionally substituted    heterocyclyl, optionally substituted heterocyclylalkyl, optionally    substituted heterocyclylalkenyl, optionally substituted    heterocyclylalkynyl, optionally substituted heteroaryl, optionally    substituted heteroarylalkyl, optionally substituted    heteroarylalkenyl, and optionally substituted heteroarylalkynyl; or    any R⁶ and R⁷, together with the common nitrogen to which they are    both attached, form an optionally substituted N-heteroaryl or an    optionally substituted N-heterocyclyl;-   R^(6a) and R^(7a) are each independently selected from the group    consisting of hydrogen, alkyl, optionally substituted cycloalkyl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, optionally substituted heteroaryl, and optionally    substituted aralkyl, and when any R^(6a) and R^(7a) are bonded to a    common nitrogen, R^(6a) and R^(7a) together with the common nitrogen    to which they are both attached, may form an optionally substituted    N-heteroaryl or an optionally substituted N-heterocyclyl;-   each R⁸ is independently selected from the group consisting of a    direct bond and an optionally substituted straight or branched    alkylene chain; and-   each R⁹ is an optionally substituted straight or branched alkylene    chain.

Of this embodiment, one embodiment is a compound of formula (Ia-1j), asset forth above, wherein:

-   n is 0 or 1;-   R^(2a) is independently selected from the group consisting of    hydrogen, optionally substituted alkyl, halo, cyano and —OR⁶;-   R³, when present, is independently selected from the group    consisting of alkyl, halo and haloalkyl;-   R⁴ is pyridinyl substituted by an N-heterocyclyl selected from the    group consisting of morpholinyl, piperazinyl, piperidinyl,    oxazepanyl, 5-oxa-2-azabicyclo[2.2.1]heptanyl and thiamorpholinyl,    where the N-heterocyclyl is optionally substituted by one or more    substituents selected from the group consisting of —C(O)R⁶,    —R⁸—N(R⁶)R⁷, —R⁸—C(O)N(R⁶)R⁷, alkyl, halo and optionally substituted    aryl;-   each R⁶ and each R⁷ is independently selected from the group    consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl,    haloalkenyl, haloalkynyl, optionally substituted cycloalkyl,    optionally substituted cycloalkylalkyl, optionally substituted aryl,    optionally substituted aralkyl, optionally substituted aralkenyl,    optionally substituted aralkynyl, optionally substituted    heterocyclyl, optionally substituted heterocyclylalkyl, optionally    substituted heterocyclylalkenyl, optionally substituted    heterocyclylalkynyl, optionally substituted heteroaryl, optionally    substituted heteroarylalkyl, optionally substituted    heteroarylalkenyl, and optionally substituted heteroarylalkynyl; or    any R⁶ and R⁷, together with the common nitrogen to which they are    both attached, form an optionally substituted N-heteroaryl or an    optionally substituted N-heterocyclyl; and-   each R⁸ is independently selected from the group consisting of a    direct bond and an optionally substituted straight or branched    alkylene chain.

A specific embodiment of this embodiment is a compound of formula(Ia-1j), as set forth above, which is4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-methyl-4-((6R,9S)-6,9-methanooctahydro-1H-pyrido[1,2-a]pyrazin-2-yl)phenyl)pyrimidin-2-amine.

Another embodiment is a compound of formula (Ia-1j), as set forth above,wherein:

-   n is 0 or 1;-   R^(2a) is independently selected from the group consisting of    hydrogen, optionally substituted alkyl, halo, cyano and —OR⁶;-   R³, when present, is independently selected from the group    consisting of alkyl, halo and haloalkyl;-   R⁴ is selected from the group consisting of naphthyridinyl,    benzo[b]azepinyl, 2,3,4,5-tetrahydro-1H-benzo[b]azepinyl,    benzo[b][1,4]oxazinyl, 3,4-dihydro-2H-benzo[b][1,4]thiazinyl,    3′,4′-dihydrospiro[cyclobutane-1,2′-pyrido[3,2-b][1,4]oxazinyl,    3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazinyl and    3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl, each optionally    substituted by one or more substituents independently selected from    the group consisting of alkyl and oxo; and-   R⁶ is selected from the group consisting of hydrogen, alkyl,    alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, optionally    substituted cycloalkyl, optionally substituted cycloalkylalkyl,    optionally substituted aryl, optionally substituted aralkyl,    optionally substituted aralkenyl, optionally substituted aralkynyl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, optionally substituted heterocyclylalkenyl,    optionally substituted heterocyclylalkynyl, optionally substituted    heteroaryl, optionally substituted heteroarylalkyl, optionally    substituted heteroarylalkenyl, and optionally substituted    heteroarylalkynyl.

A specific embodiment of this embodiment is a compound of formula(Ia-1j) selected from the group consisting of:

-   4-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-N-(3-methyl-4-((6R,9S)-6,9-methanooctahydro-1H-pyrido[1,2-a]pyrazin-2-yl)phenyl)pyrimidin-2-amine;-   4-(2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-yl)-N-(3-methyl-4-((6R,9S)-6,9-methanooctahydro-1H-pyrido[1,2-a]pyrazin-2-yl)phenyl)pyrimidin-2-amine;-   4-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-7-yl)-N-(3-methyl-4-((6R,9S)-6,9-methanooctahydro-1H-pyrido[1,2-a]pyrazin-2-yl)phenyl)pyrimidin-2-amine.

Another embodiment of the compounds of formula (Ia-1), as set forthabove, is a compound according to formula (Ia-1k):

wherein n is 0 or 1;

-   R^(2a) is independently selected from the group consisting of    hydrogen, optionally substituted alkyl, halo, cyano and —OR⁶;-   R³, when present, is independently selected from the group    consisting of alkyl, halo and haloalkyl;-   R⁴ is selected from the group consisting of phenyl, benzimidazolyl,    benzo[b][1,4]oxazinyl, benzo[b]azepinyl,    2,3,4,5-tetrahydro-1H-benzo[b]azepinyl,    3,4-dihydro-2H-benzo[b][1,4]thiazinyl,    3′,4′-dihydrospiro[cyclobutane-1,2′-pyrido[3,2-b][1,4]oxazinyl,    3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl,    3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazinyl, imidazo[1,2-a]pyridinyl,    6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indolyl,    7,8,9,9a-tetrahydro-5H-pyrido[2,3-e]pyrrolo[1,2-a][1,4]diazepin-10(11H)-onyl,    indolyl, indolinyl, naphthyridinyl, pyrazolyl, pyridinyl, pyrazinyl,    pyrimidinyl, pyrrolyl, 1H-pyrrolo[2,3-b]pyridinyl, and thiazolyl,    each optionally substituted by one or more substituents    independently selected from the group consisting of oxo, alkyl,    halo, haloalkyl, cyano, N-heterocyclyl, N-heteroaryl, aryl,    —R⁸—OR^(6a), —R⁸—S(O)_(p)R^(6a) (where p is 0, 1 or 2),    —R⁸—C(O)R^(6a), —R⁸—C(O)OR^(6a), —R⁸—C(O)N(R^(6a))R^(7a),    —R⁸—N(R^(6a))R^(7a), —R⁸—N(R^(6a))—R⁹—N(R^(6a))R^(7a),    —R⁸—N(R^(6a))—R⁹—OR^(7a), —R⁸—N(R^(6a))C(O)R^(7a),    —R⁸—N(R^(6a))S(O)₂R^(7a), —R⁸—N(R^(6a))C(O)—R⁸—N(R^(6a))R^(7a), and    —R⁸—N(R^(6a))—R⁹—N(R^(6a))S(O)₂R^(7a), where the N-heterocyclyl, the    N-heteroaryl and the aryl are each independently optionally    substituted by one or more substituents selected from the group    consisting of —C(O)R⁶, —R⁸—N(R⁶)R⁷, —R⁸—C(O)N(R⁶)R⁷, alkyl, halo and    optionally substituted aryl;-   R^(5a) is selected from the group consisting of hydrogen, alkyl,    alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, optionally    substituted aryl, optionally substituted aralkyl, optionally    substituted aralkenyl, optionally substituted aralkynyl, optionally    substituted cycloalkyl, optionally substituted cycloalkylalkyl,    optionally substituted cycloalkylalkenyl, optionally substituted    cycloalkylalkynyl, optionally substituted heterocyclyl, optionally    substituted heterocyclylalkyl, optionally substituted    heterocyclylalkenyl, optionally substituted heterocyclylalkynyl,    optionally substituted heteroaryl, optionally substituted    heteroarylalkyl, optionally substituted heteroarylalkenyl,    optionally substituted heteroarylalkynyl, —R⁸—OR⁶, —R⁸—C(O)R⁶,    —R⁸—C(O)OR⁶, —R⁹—N(R⁶)R⁷, —R⁸—C(O)N(R⁶)R⁷, —R⁸—C(N═R⁶)N(R⁶)R⁷,    —R⁸—S(O)₂N(R⁶)R⁷, and —R⁸—S(O)_(t)R⁶ (where t is 1 or 2);-   each R⁶ and each R⁷ is independently selected from the group    consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl,    haloalkenyl, haloalkynyl, optionally substituted cycloalkyl,    optionally substituted cycloalkylalkyl, optionally substituted aryl,    optionally substituted aralkyl, optionally substituted aralkenyl,    optionally substituted aralkynyl, optionally substituted    heterocyclyl, optionally substituted heterocyclylalkyl, optionally    substituted heterocyclylalkenyl, optionally substituted    heterocyclylalkynyl, optionally substituted heteroaryl, optionally    substituted heteroarylalkyl, optionally substituted    heteroarylalkenyl, and optionally substituted heteroarylalkynyl; or    any R⁶ and R⁷, together with the common nitrogen to which they are    both attached, form an optionally substituted N-heteroaryl or an    optionally substituted N-heterocyclyl;-   R^(6a) and R^(7a) are each independently selected from the group    consisting of hydrogen, alkyl, optionally substituted cycloalkyl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, optionally substituted heteroaryl, and optionally    substituted aralkyl, and when any R^(6a) and R^(7a) are bonded to a    common nitrogen, R^(6a) and R^(7a) together with the common nitrogen    to which they are both attached, may form an optionally substituted    N-heteroaryl or an optionally substituted N-heterocyclyl;-   each R⁸ is independently selected from the group consisting of a    direct bond and an optionally substituted straight or branched    alkylene chain; and-   each R⁹ is an optionally substituted straight or branched alkylene    chain.

Of this embodiment, one embodiment is a compound of formula (Ia-1k), asset forth above, wherein:

-   n is 0 or 1;-   R^(2a) is independently selected from the group consisting of    hydrogen, optionally substituted alkyl, halo, cyano and —OR⁶;-   R³, when present, is independently selected from the group    consisting of alkyl, halo and haloalkyl;-   R⁴ is pyridinyl substituted by an N-heterocyclyl selected from the    group consisting of morpholinyl, piperazinyl, piperidinyl,    oxazepanyl, 5-oxa-2-azabicyclo[2.2.1]heptanyl and thiamorpholinyl,    where the N-heterocyclyl is optionally substituted by one or more    substituents selected from the group consisting of —C(O)R⁶,    —R⁸—N(R⁶)R⁷, —R⁸—C(O)N(R⁶)R⁷, alkyl, halo and optionally substituted    aryl;-   R^(5a) is independently selected from the group consisting of    hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl,    optionally substituted cycloalkylalkyl, —R⁸—C(O)R⁶, —R⁸—C(O)N(R⁶)R⁷,    —R⁸—C(N═R⁶)N(R⁶)R⁷ and —R⁸—S(O)_(t)R⁶ (where t is 1 or 2);-   each R⁶ and each R⁷ is independently selected from the group    consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl,    haloalkenyl, haloalkynyl, optionally substituted cycloalkyl,    optionally substituted cycloalkylalkyl, optionally substituted aryl,    optionally substituted aralkyl, optionally substituted aralkenyl,    optionally substituted aralkynyl, optionally substituted    heterocyclyl, optionally substituted heterocyclylalkyl, optionally    substituted heterocyclylalkenyl, optionally substituted    heterocyclylalkynyl, optionally substituted heteroaryl, optionally    substituted heteroarylalkyl, optionally substituted    heteroarylalkenyl, and optionally substituted heteroarylalkynyl; or    any R⁶ and R⁷, together with the common nitrogen to which they are    both attached, form an optionally substituted N-heteroaryl or an    optionally substituted N-heterocyclyl; and-   each R⁸ is independently selected from the group consisting of a    direct bond and an optionally substituted straight or branched    alkylene chain.

A specific embodiment of this embodiment is a compound of formula(Ia-1k) which is4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-cyano-4-(3,9-diazabicyclo[3.3.2]decan-10-on-3-yl)phenyl)pyrimidin-2-amine.

Another embodiment is a compound of formula (Ia-1k), as set forth above,wherein:

-   n is 0 or 1;-   R^(2a) is independently selected from the group consisting of    hydrogen, optionally substituted alkyl, halo, cyano and —OR⁶;-   R³, when present, is independently selected from the group    consisting of alkyl, halo and haloalkyl;-   R⁴ is selected from the group consisting of naphthyridinyl,    benzo[b]azepinyl, 2,3,4,5-tetrahydro-1H-benzo[b]azepinyl,    benzo[b][1,4]oxazinyl, 3,4-dihydro-2H-benzo[b][1,4]thiazinyl,    3′,4′-dihydrospiro[cyclobutane-1,2′-pyrido[3,2-b][1,4]oxazinyl,    3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazinyl,    6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indolyl,    7,8,9,9a-tetrahydro-5H-pyrido[2,3-e]pyrrolo[1,2-a][1,4]diazepin-10(11H)-onyl,    and 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl, each optionally    substituted by one or more substituents independently selected from    the group consisting of alkyl and oxo;-   R^(5a) is independently selected from the group consisting of    hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl,    optionally substituted cycloalkylalkyl, —R⁸—C(O)R⁶, —R⁸—C(O)N(R⁶)R⁷,    —R⁸—C(N═R⁶)N(R⁶)R⁷ and —R⁸—S(O)_(t)R⁶ (where t is 1 or 2);-   each R⁶ and each R⁷ is independently selected from the group    consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl,    haloalkenyl, haloalkynyl, optionally substituted cycloalkyl,    optionally substituted cycloalkylalkyl, optionally substituted aryl,    optionally substituted aralkyl, optionally substituted aralkenyl,    optionally substituted aralkynyl, optionally substituted    heterocyclyl, optionally substituted heterocyclylalkyl, optionally    substituted heterocyclylalkenyl, optionally substituted    heterocyclylalkynyl, optionally substituted heteroaryl, optionally    substituted heteroarylalkyl, optionally substituted    heteroarylalkenyl, and optionally substituted heteroarylalkynyl; or    any R⁶ and R⁷, together with the common nitrogen to which they are    both attached, form an optionally substituted N-heteroaryl or an    optionally substituted N-heterocyclyl; and-   each R⁸ is independently selected from the group consisting of a    direct bond and an optionally substituted straight or branched    alkylene chain.

A specific embodiment of this embodiment is a compound of formula(Ia-1k) which is4-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(3-cyano-4-(3,9-diazabicyclo[3.3.2]decan-10-on-3-yl)phenyl)pyrimidin-2-amine.

Another embodiment of the compounds of formula (Ia-1), as set forthabove, is a compound according to formula (Ia-1l):

wherein n is 0 or 1;

-   R^(2a) is independently selected from the group consisting of    hydrogen, optionally substituted alkyl, halo, cyano and —OR⁶;-   R³, when present, is independently selected from the group    consisting of alkyl, halo and haloalkyl;-   R⁴ is selected from the group consisting of phenyl, benzimidazolyl,    benzo[b][1,4]oxazinyl, benzo[b]azepinyl,    2,3,4,5-tetrahydro-1H-benzo[b]azepinyl,    3,4-dihydro-2H-benzo[b][1,4]thiazinyl,    3′,4′-dihydrospiro[cyclobutane-1,2′-pyrido[3,2-b][1,4]oxazinyl,    3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl,    3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazinyl, imidazo[1,2-a]pyridinyl,    6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indolyl,    7,8,9,9a-tetrahydro-5H-pyrido[2,3-e]pyrrolo[1,2-a][1,4]diazepin-10(11H)-onyl,    indolyl, indolinyl, naphthyridinyl, pyrazolyl, pyridinyl, pyrazinyl,    pyrimidinyl, pyrrolyl, 1H-pyrrolo[2,3-b]pyridinyl, and thiazolyl,    each optionally substituted by one or more substituents    independently selected from the group consisting of oxo, alkyl,    halo, haloalkyl, cyano, N-heterocyclyl, N-heteroaryl, aryl,    —R⁸—OR^(6a), —R⁸—S(O)_(p)R^(6a) (where p is 0, 1 or 2),    —R⁸—C(O)R^(6a), —R⁸—C(O)OR^(6a), —R⁸—C(O)N(R^(6a))R^(7a),    —R⁸—N(R^(6a))R^(7a), —R⁸—N(R^(6a))—R⁹—N(R^(6a))R^(7a),    —R⁸—N(R^(6a))—R⁹—OR^(7a), —R⁸—N(R^(6a))C(O)R^(7a),    —R⁸—N(R^(6a))S(O)₂R^(7a), —R⁸—N(R^(6a))C(O)—R⁸—N(R^(6a))R^(7a), and    —R⁸—N(R^(6a))—R⁹—N(R^(6a))S(O)₂R^(7a), where the N-heterocyclyl, the    N-heteroaryl and the aryl are each independently optionally    substituted by one or more substituents selected from the group    consisting of —C(O)R⁶, —R⁸—N(R⁶)R⁷, —R⁸—C(O)N(R⁶)R⁷, alkyl, halo and    optionally substituted aryl;-   R^(5a) is selected from the group consisting of hydrogen, alkyl,    alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, optionally    substituted aryl, optionally substituted aralkyl, optionally    substituted aralkenyl, optionally substituted aralkynyl, optionally    substituted cycloalkyl, optionally substituted cycloalkylalkyl,    optionally substituted cycloalkylalkenyl, optionally substituted    cycloalkylalkynyl, optionally substituted heterocyclyl, optionally    substituted heterocyclylalkyl, optionally substituted    heterocyclylalkenyl, optionally substituted heterocyclylalkynyl,    optionally substituted heteroaryl, optionally substituted    heteroarylalkyl, optionally substituted heteroarylalkenyl,    optionally substituted heteroarylalkynyl, —R⁸—OR⁶, —R⁸—C(O)R⁶,    —R⁸—C(O)OR⁶, —R⁸—N(R⁶)R⁷, —R⁸—C(O)N(R⁶)R⁷, —R⁸—C(N═R⁶)N(R⁶)R⁷,    —R⁸—S(O)₂N(R⁶)R⁷, and —R⁸—S(O)_(t)R⁶ (where t is 1 or 2);-   each R⁶ and each R⁷ is independently selected from the group    consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl,    haloalkenyl, haloalkynyl, optionally substituted cycloalkyl,    optionally substituted cycloalkylalkyl, optionally substituted aryl,    optionally substituted aralkyl, optionally substituted aralkenyl,    optionally substituted aralkynyl, optionally substituted    heterocyclyl, optionally substituted heterocyclylalkyl, optionally    substituted heterocyclylalkenyl, optionally substituted    heterocyclylalkynyl, optionally substituted heteroaryl, optionally    substituted heteroarylalkyl, optionally substituted    heteroarylalkenyl, and optionally substituted heteroarylalkynyl; or    any R⁶ and R⁷, together with the common nitrogen to which they are    both attached, form an optionally substituted N-heteroaryl or an    optionally substituted N-heterocyclyl;-   each R^(6a) and R^(7a) is independently selected from the group    consisting of hydrogen, alkyl, optionally substituted cycloalkyl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, optionally substituted heteroaryl, and optionally    substituted aralkyl;-   each R⁸ is independently selected from the group consisting of a    direct bond and an optionally substituted straight or branched    alkylene chain; and-   each R⁹ is an optionally substituted straight or branched alkylene    chain.

Of this embodiment, one embodiment is a compound of formula (Ia-1l), asset forth above, wherein:

-   n is 0 or 1;-   R^(2a) is independently selected from the group consisting of    hydrogen, optionally substituted alkyl, halo, cyano and —OR⁶;-   R³, when present, is independently selected from the group    consisting of alkyl, halo and haloalkyl;-   R⁴ is pyridinyl substituted by one or more substituents selected    from the group consisting of alkyl, haloalkyl, cyano, —R⁸—OR^(6a),    —R⁸—N(R^(6a))R^(7a), —R⁸—N(R^(6a))—R⁹—N(R^(6a))R^(7a) and    —R⁸—N(R^(6a))—R⁹—OR^(7a);-   R^(5a) is independently selected from the group consisting of    hydrogen, alkyl, —R⁹—N(R⁶)R⁷ and optionally substituted    heterocyclyl;-   each R⁶ and each R⁷ is independently selected from the group    consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl,    haloalkenyl, haloalkynyl, optionally substituted cycloalkyl,    optionally substituted cycloalkylalkyl, optionally substituted aryl,    optionally substituted aralkyl, optionally substituted aralkenyl,    optionally substituted aralkynyl, optionally substituted    heterocyclyl, optionally substituted heterocyclylalkyl, optionally    substituted heterocyclylalkenyl, optionally substituted    heterocyclylalkynyl, optionally substituted heteroaryl, optionally    substituted heteroarylalkyl, optionally substituted    heteroarylalkenyl, and optionally substituted heteroarylalkynyl; or    any R⁶ and R⁷, together with the common nitrogen to which they are    both attached, form an optionally substituted N-heteroaryl or an    optionally substituted N-heterocyclyl;-   R^(6a) and R^(7a) are each independently selected from the group    consisting of hydrogen, alkyl, optionally substituted cycloalkyl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, optionally substituted heteroaryl, and optionally    substituted aralkyl, and when any R^(6a) and R^(7a) are bonded to a    common nitrogen, R^(6a) and R^(7a) together with the common nitrogen    to which they are both attached, may form an optionally substituted    N-heteroaryl or an optionally substituted N-heterocyclyl;-   each R⁸ is independently selected from the group consisting of a    direct bond and an optionally substituted straight or branched    alkylene chain; and-   each R⁹ is an optionally substituted straight or branched alkylene    chain.

A specific embodiment of this embodiment is a compound of formula(Ia-1l) selected from the group consisting of:

-   4-(6-(tetrahydropyran-4-yloxy)pyridin-3-yl)-N-(3-methyl-4-(3-(dimethylamino)-8-azabicyclo[3.2.1]octan-8-yl)phenyl)pyrimidin-2-amine;    and-   4-(6-(tetrahydropyran-4-yloxy)pyridin-3-yl)-N-(3-methyl-4-(3-(morpholin-4-yl)-8-azabicyclo[3.2.1]octan-8-yl)phenyl)pyrimidin-2-amine.

Another embodiment is a compound of formula (Ia-1 I), as set forthabove, wherein:

-   n is 0 or 1;-   R^(2a) is independently selected from the group consisting of    hydrogen, optionally substituted alkyl, halo, cyano and —OR⁶;-   R³, when present, is independently selected from the group    consisting of alkyl, halo and haloalkyl;-   R⁴ is pyridinyl substituted by an N-heterocyclyl selected from the    group consisting of morpholinyl, piperazinyl, piperidinyl,    oxazepanyl, 5-oxa-2-azabicyclo[2.2.1]heptanyl and thiamorpholinyl,    where the N-heterocyclyl is optionally substituted by one or more    substituents selected from the group consisting of —C(O)R⁶,    —R⁹—N(R⁶)R⁷, —R⁹—C(O)N(R⁶)R⁷, alkyl, halo and optionally substituted    aryl;-   R^(5a) is independently selected from the group consisting of    hydrogen, alkyl, —R⁹—N(R⁶)R⁷ and optionally substituted    heterocyclyl;-   each R⁶ and each R⁷ is independently selected from the group    consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl,    haloalkenyl, haloalkynyl, optionally substituted cycloalkyl,    optionally substituted cycloalkylalkyl, optionally substituted aryl,    optionally substituted aralkyl, optionally substituted aralkenyl,    optionally substituted aralkynyl, optionally substituted    heterocyclyl, optionally substituted heterocyclylalkyl, optionally    substituted heterocyclylalkenyl, optionally substituted    heterocyclylalkynyl, optionally substituted heteroaryl, optionally    substituted heteroarylalkyl, optionally substituted    heteroarylalkenyl, and optionally substituted heteroarylalkynyl; or    any R⁶ and R⁷, together with the common nitrogen to which they are    both attached, form an optionally substituted N-heteroaryl or an    optionally substituted N-heterocyclyl;-   each R⁸ is independently selected from the group consisting of a    direct bond and an optionally substituted straight or branched    alkylene chain; and-   each R⁹ is an optionally substituted straight or branched alkylene    chain.

A specific embodiment of this embodiment is a compound of formula(Ia-1l) selected from the group consisting of:

-   4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-methyl-4-(3-(morpholin-4-yl)-8-azabicyclo[3.2.1]octan-8-yl)phenyl)pyrimidin-2-amine;    and-   4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-methyl-4-(3-(dimethylamino)-8-azabicyclo[3.2.1]octan-8-yl)phenyl)pyrimidin-2-amine.

Of the compounds of formula (Ia-1), as set forth above, anotherembodiment is a compound wherein:

-   n is 0 or 1;-   m is 0 or 1;-   R¹ is selected from the group consisting of hydrogen or alkyl;-   R², when present, is independently selected from the group    consisting of optionally substituted alkyl, halo, cyano and —OR⁶;-   R³, when present, is independently selected from the group    consisting of alkyl, halo and haloalkyl;-   R⁴ is heteroaryl optionally substituted by a bridged N-heterocyclyl,    where the bridged N-heterocyclyl is optionally substituted by one or    more substituents selected from the group consisting of alkyl, halo    and optionally substituted aryl;-   R⁵ is a non-bridged N-heterocyclyl, wherein a nitrogen atom in the    non-bridged N-heterocyclyl is optionally substituted by a    substituent selected from the group consisting of alkyl, optionally    substituted aryl, optionally substituted aralkyl, optionally    substituted cycloalkyl, optionally substituted cycloalkylalkyl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, optionally substituted heteroaryl, optionally    substituted heteroarylalkyl, —R⁸—C(O)R⁶, —R⁸—C(O)OR⁶, —R⁹—N(R⁶)R⁷,    —R⁸—C(O)N(R⁶)R⁷, —R⁸—S(O)₂N(R⁶)R⁷, and —R⁸—S(O)_(t)R⁶ (where t is 1    or 2); and wherein a carbon atom in the non-bridged N-heterocyclyl    is optionally substituted by a substituent selected from the group    consisting of alkyl, halo, haloalkyl, optionally substituted aryl,    optionally substituted aralkyl, optionally substituted cycloalkyl,    optionally substituted cycloalkylalkyl, optionally substituted    heterocyclyl, optionally substituted heterocyclylalkyl, optionally    substituted heteroaryl, optionally substituted heteroarylalkyl,    —R⁸—OR⁶, —R⁸—C(O)R⁶, —R⁸—C(O)OR⁶, —R⁹—N(R⁶)R⁷, —R⁸—C(O)N(R⁶)R⁷,    —R⁸—S(O)₂N(R⁶)R⁷, and —R⁸—S(O)_(p)R⁶ (where p is 0, 1 or 2);-   each R⁶ and each R⁷ is independently selected from the group    consisting of hydrogen, alkyl, haloalkyl, optionally substituted    cycloalkyl, optionally substituted cycloalkylalkyl, optionally    substituted aryl, optionally substituted aralkyl, optionally    substituted heterocyclyl, optionally substituted heterocyclylalkyl,    optionally substituted heteroaryl and optionally substituted    heteroarylalkyl; or any R⁶ and R⁷, together with the common nitrogen    to which they are both attached, form an optionally substituted    N-heteroaryl or an optionally substituted N-heterocyclyl;-   each R⁸ is independently selected from the group consisting of a    direct bond and an optionally substituted straight or branched    alkylene chain; and-   each R⁹ is an optionally substituted straight or branched alkylene    chain.

Of this embodiment, one embodiment is a compound of formula (Ia-1)wherein:

-   n is 0 or 1;-   m is 1;-   R¹ is selected from the group consisting of hydrogen or alkyl;-   R² is alkyl;-   R³, when present, is independently selected from the group    consisting of alkyl, halo and haloalkyl;-   R⁴ is pyridinyl substituted by a bridged N-heterocyclyl, where the    bridged N-heterocyclyl is optionally substituted by one or more    substituents selected from the group consisting of alkyl, halo and    optionally substituted aryl; and-   R⁵ is a non-bridged N-heterocyclyl selected from the group    consisting of piperazinyl, piperidinyl and morpholinyl.

A specific embodiment of this embodiment is a compound of formula (Ia-1)selected from the group consisting of:

-   4-(6-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)-N-(3-methyl-4-(4-methylpiperazin-1-yl)phenyl)pyrimidin-2-amine;    and-   4-(6-((1S,4S)-5-(4-fluorophenyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)-N-(3-methyl-4-(4-methylpiperazin-1-yl)phenyl)pyrimidin-2-amine.

Another embodiment of the invention is a compound of formula (Ia), asset forth above in the Summary of the Invention, according to formula(Ia-2):

wherein:

-   n is 0, 1 or 2;-   m is 0, 1 or 2;-   R¹ is selected from the group consisting of hydrogen, alkyl,    alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkenyl, optionally    substituted cycloalkyl, optionally substituted cycloalkylalkyl,    optionally substituted cycloalkylalkenyl, optionally substituted    cycloalkylalkynyl, optionally substituted aryl, optionally    substituted aralkyl, optionally substituted aralkenyl, optionally    substituted aralkynyl, —R⁸—C(O)OR⁶, —R⁹—N(R⁶)R⁷ and —R⁹—OR⁶;-   each R², when present, is independently selected from the group    consisting of optionally substituted alkyl, halo, cyano and —OR⁶;-   each R³, when present, is independently selected from the group    consisting of alkyl, halo and haloalkyl;-   R⁴ is selected from the group consisting of aryl and heteroaryl,    where the aryl and the heteroaryl are each independently optionally    substituted by one or more substituents selected from the group    consisting of oxo, alkyl, halo, haloalkyl, cyano, N-heterocyclyl,    N-heteroaryl, aryl, —R⁸—OR^(6a), —R⁸—S(O)_(p)R^(6a) (where p is 0, 1    or 2), —R⁸—C(O)R^(6a), —R⁸—C(O)OR^(6a), —R⁸—C(O)N(R^(6a))R^(7a),    —R⁸—N(R^(6a))R^(7a), —R⁸—N(R^(6a))—R⁹—N(R^(6a))R^(7a),    —R⁸—N(R^(6a))—R⁹—OR^(7a), —R⁸—N(R^(6a))C(O)R^(7a),    —R⁸—N(R^(6a))S(O)₂R^(7a), —R⁸—N(R^(6a))C(O)—R⁸—N(R^(6a))R^(7a), and    —R⁸—N(R^(6a))—R⁹—N(R^(6a))S(O)₂R^(7a), where each R^(6a) and R^(7a)    is independently selected from the group consisting of hydrogen,    alkyl, optionally substituted cycloalkyl, optionally substituted    heterocyclyl, optionally substituted heterocyclylalkyl, optionally    substituted heteroaryl and optionally substituted aralkyl, and where    the N-heterocyclyl, the N-heteroaryl and the aryl are each    independently optionally substituted by one or more substituents    selected from the group consisting of —C(O)R⁶, —R⁸—N(R⁶)R⁷,    —R⁸—C(O)N(R⁶)R⁷, alkyl, halo and optionally substituted aryl;-   R⁵ is an N-heterocyclyl, wherein a nitrogen atom in the    N-heterocyclyl is optionally substituted by a substituent selected    from the group consisting of alkyl, alkenyl, alkynyl, haloalkyl,    haloalkenyl, haloalkynyl, optionally substituted aryl, optionally    substituted aralkyl, optionally substituted aralkenyl, optionally    substituted aralkynyl, optionally substituted cycloalkyl, optionally    substituted cycloalkylalkyl, optionally substituted    cycloalkylalkenyl, optionally substituted cycloalkylalkynyl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, optionally substituted heterocyclylalkenyl,    optionally substituted heterocyclylalkynyl, optionally substituted    heteroaryl, optionally substituted heteroarylalkyl, optionally    substituted heteroarylalkenyl, optionally substituted    heteroarylalkynyl, —R⁸—OR⁶, —R⁸—C(O)R⁶, —R⁸—C(O)OR⁶, —R⁹—N(R⁶)R⁷,    —R⁸—C(O)N(R⁶)R⁷, —R⁸—C(N═R⁶)N(R⁶)R⁷, —R⁸—S(O)₂N(R⁶)R⁷, and    —R⁸—S(O)_(t)R⁶ (where t is 1 or 2); and a carbon atom in the    N-heterocyclyl is optionally substituted by a substituent selected    from the group consisting of alkyl, alkenyl, alkynyl, halo,    haloalkyl, haloalkenyl, haloalkynyl, oxo, optionally substituted    aryl, optionally substituted aralkyl, optionally substituted    aralkenyl, optionally substituted aralkynyl, optionally substituted    cycloalkyl, optionally substituted cycloalkylalkyl, optionally    substituted cycloalkylalkenyl, optionally substituted    cycloalkylalkynyl, optionally substituted heterocyclyl, optionally    substituted heterocyclylalkyl, optionally substituted    heterocyclylalkenyl, optionally substituted heterocyclylalkynyl,    optionally substituted heteroaryl, optionally substituted    heteroarylalkyl, optionally substituted heteroarylalkenyl,    optionally substituted heteroarylalkynyl, —R⁸—OR⁶, —R⁸—C(O)R⁶,    —R⁸—C(O)OR⁶, —R⁹—N(R⁶)R⁷, —R⁸—C(O)N(R⁶)R⁷, —R⁸—S(O)₂N(R⁶)R⁷, and    —R⁸—S(O)_(p)R⁶ (where p is 0, 1 or 2);-   each R⁶ and each R⁷ is independently selected from the group    consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl,    haloalkenyl, haloalkynyl, optionally substituted cycloalkyl,    optionally substituted cycloalkylalkyl, optionally substituted aryl,    optionally substituted aralkyl, optionally substituted aralkenyl,    optionally substituted aralkynyl, optionally substituted    heterocyclyl, optionally substituted heterocyclylalkyl, optionally    substituted heterocyclylalkenyl, optionally substituted    heterocyclylalkynyl, optionally substituted heteroaryl, optionally    substituted heteroarylalkyl, optionally substituted    heteroarylalkenyl, and optionally substituted heteroarylalkynyl; or    any R⁶ and R⁷, together with the common nitrogen to which they are    both attached, form an optionally substituted N-heteroaryl or an    optionally substituted N-heterocyclyl;-   each R⁸ is independently selected from the group consisting of a    direct bond, an optionally substituted straight or branched alkylene    chain, an optionally substituted straight or branched alkenylene    chain and an optionally substituted straight or branched alkynylene    chain; and-   each R⁹ is independently selected from the group consisting of an    optionally substituted straight or branched alkylene chain, an    optionally substituted straight or branched alkenylene chain and an    optionally substituted straight or branched alkynylene chain;-   provided at least one of R⁵ and a substituent on R⁴ is a bridged    N-heterocyclyl;

Of the compounds of formula (Ia-2), as set forth above, one embodimentis a compound selected from the following:

wherein:

-   each n is 0, 1 or 2;-   each m is 0, 1 or 2;-   each R², when present, is independently selected from the group    consisting of optionally substituted alkyl, halo, cyano and —OR⁶;-   each R³, when present, is independently selected from the group    consisting of alkyl, halo and haloalkyl;-   each R⁴ is independently selected from the group consisting of aryl    and heteroaryl, where the aryl and the heteroaryl are each    independently optionally substituted by one or more substituents    selected from the group consisting of oxo, alkyl, halo, haloalkyl,    cyano, N-heterocyclyl, N-heteroaryl, aryl, —R⁸—OR^(6a),    —R⁸—S(O)_(p)R^(6a) (where p is 0, 1 or 2), —R⁸—C(O)R^(6a),    —R⁸—C(O)OR^(6a), —R⁸—C(O)N(R^(6a))R^(7a), —R⁸—N(R^(6a))R^(7a),    —R⁸—N(R^(6a))—R⁹—N(R^(6a))R^(7a), —R⁸—N(R^(6a))—R⁹—OR^(7a),    —R⁸—N(R^(6a))C(O)R^(7a), —R⁸—N(R^(6a))S(O)₂R^(7a),    —R⁸—N(R^(6a))C(O)—R⁸—N(R^(6a))R^(7a), and    —R⁸—N(R^(6a))—R⁹—N(R^(6a))S(O)₂R^(7a), where each R^(6a) and R^(7a)    is independently selected from the group consisting of hydrogen,    alkyl, optionally substituted cycloalkyl, optionally substituted    heterocyclyl, optionally substituted heterocyclylalkyl, optionally    substituted heteroaryl and optionally substituted aralkyl, and where    the N-heterocyclyl, the N-heteroaryl and the aryl are each    independently optionally substituted by one or more substituents    selected from the group consisting of —C(O)R⁶, —R⁸—N(R⁶)R⁷,    —R⁸—C(O)N(R⁶)R⁷, alkyl, halo and optionally substituted aryl;-   each R^(5a) is independently selected from the group consisting of    hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl,    haloalkynyl, optionally substituted aryl, optionally substituted    aralkyl, optionally substituted aralkenyl, optionally substituted    aralkynyl, optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted cycloalkylalkenyl,    optionally substituted cycloalkylalkynyl, optionally substituted    heterocyclyl, optionally substituted heterocyclylalkyl, optionally    substituted heterocyclylalkenyl, optionally substituted    heterocyclylalkynyl, optionally substituted heteroaryl, optionally    substituted heteroarylalkyl, optionally substituted    heteroarylalkenyl, optionally substituted heteroarylalkynyl,    —R⁸—OR⁶, —R⁸—C(O)R⁶, —R⁸—C(O)OR⁶, —R⁹—N(R⁶)R⁷, —R⁸—C(O)N(R⁶)R⁷,    —R⁸—C(N═R⁶)N(R⁶)R⁷, —R⁸—S(O)₂N(R⁶)R⁷, and —R⁸—S(O)_(t)R⁶ (where t is    1 or 2);-   each R⁶ and each R⁷ is independently selected from the group    consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl,    haloalkenyl, haloalkynyl, optionally substituted cycloalkyl,    optionally substituted cycloalkylalkyl, optionally substituted aryl,    optionally substituted aralkyl, optionally substituted aralkenyl,    optionally substituted aralkynyl, optionally substituted    heterocyclyl, optionally substituted heterocyclylalkyl, optionally    substituted heterocyclylalkenyl, optionally substituted    heterocyclylalkynyl, optionally substituted heteroaryl, optionally    substituted heteroarylalkyl, optionally substituted    heteroarylalkenyl, and optionally substituted heteroarylalkynyl; or    any R⁶ and R⁷, together with the common nitrogen to which they are    both attached, form an optionally substituted N-heteroaryl or an    optionally substituted N-heterocyclyl;-   each R⁸ is independently selected from the group consisting of a    direct bond, an optionally substituted straight or branched alkylene    chain, an optionally substituted straight or branched alkenylene    chain and an optionally substituted straight or branched alkynylene    chain; and-   each R⁹ is independently selected from the group consisting of an    optionally substituted straight or branched alkylene chain, an    optionally substituted straight or branched alkenylene chain and an    optionally substituted straight or branched alkynylene chain.

Of this embodiment, one embodiment is a compound selected from theformulae above wherein:

-   each n is 0 or 1;-   each m is 0 or 1;-   each R⁴ is independently selected from the group consisting of    phenyl, benzimidazolyl, benzo[b][1,4]oxazinyl, benzo[b]azepinyl,    2,3,4,5-tetrahydro-1H-benzo[b]azepinyl,    3,4-dihydro-2H-benzo[b][1,4]thiazinyl,    3′,4′-dihydrospiro[cyclobutane-1,2′-pyrido[3,2-b][1,4]oxazinyl,    3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl,    3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazinyl, imidazo[1,2-a]pyridinyl,    6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indolyl,    7,8,9,9a-tetrahydro-5H-pyrido[2,3-e]pyrrolo[1,2-a][1,4]diazepin-10(11H)-onyl,    indolyl, indolinyl, naphthyridinyl, pyrazolyl, pyridinyl, pyrazinyl,    pyrimidinyl, pyrrolyl, 1H-pyrrolo[2,3-b]pyridinyl, and thiazolyl,    each optionally substituted by one or more substituents    independently selected from the group consisting of oxo, alkyl,    halo, haloalkyl, cyano, N-heterocyclyl, N-heteroaryl, aryl,    —R⁸—OR^(6a), —R⁸—S(O)_(p)R^(6a) (where p is 0, 1 or 2),    —R⁸—C(O)R^(6a), —R⁸—C(O)OR^(6a), —R⁸—C(O)N(R^(6a))R^(7a),    —R⁸—N(R^(6a))R^(7a), —R⁸—N(R^(6a))—R⁹—N(R^(6a))R^(7a),    —R⁸—N(R^(6a))—R⁹—OR^(7a), —R⁸—N(R^(6a))C(O)R^(7a),    —R⁸—N(R^(6a))S(O)₂R^(7a), —R⁸—N(R^(6a))C(O)—R⁸—N(R^(6a))R^(7a), and    —R⁸—N(R^(6a))—R⁹—N(R^(6a))S(O)₂R^(7a), where the N-heterocyclyl, the    N-heteroaryl and the aryl are each independently optionally    substituted by one or more substituents selected from the group    consisting of —C(O)R⁶, —R⁸—N(R⁶)R⁷, —R⁸— C(O)N(R⁶)R⁷, alkyl, halo    and optionally substituted aryl;-   each R⁶ and each R⁷ is independently selected from the group    consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl,    haloalkenyl, haloalkynyl, optionally substituted cycloalkyl,    optionally substituted cycloalkylalkyl, optionally substituted aryl,    optionally substituted aralkyl, optionally substituted aralkenyl,    optionally substituted aralkynyl, optionally substituted    heterocyclyl, optionally substituted heterocyclylalkyl, optionally    substituted heterocyclylalkenyl, optionally substituted    heterocyclylalkynyl, optionally substituted heteroaryl, optionally    substituted heteroarylalkyl, optionally substituted    heteroarylalkenyl, and optionally substituted heteroarylalkynyl; or    any R⁶ and R⁷, together with the common nitrogen to which they are    both attached, form an optionally substituted N-heteroaryl or an    optionally substituted N-heterocyclyl;-   each R^(6a) and R^(7a) is independently selected from the group    consisting of hydrogen, alkyl, optionally substituted cycloalkyl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, optionally substituted heteroaryl, and optionally    substituted aralkyl;-   each R⁸ is independently selected from the group consisting of a    direct bond and an optionally substituted straight or branched    alkylene chain; and-   each R⁹ is an optionally substituted straight or branched alkylene    chain.

One embodiment of the compounds of formula (Ia-2), as set forth above,is a compound according to formula (Ia-2a):

-   n is 0 or 1;-   m is 0 or 1;-   R², when present, is independently selected from the group    consisting of optionally substituted alkyl, halo, cyano and —OR⁶;-   R³, when present, is independently selected from the group    consisting of alkyl, halo and haloalkyl;-   R⁴ is selected from the group consisting of phenyl, benzimidazolyl,    benzo[b][1,4]oxazinyl, benzo[b]azepinyl,    2,3,4,5-tetrahydro-1H-benzo[b]azepinyl,    3,4-dihydro-2H-benzo[b][1,4]thiazinyl,    3′,4′-dihydrospiro[cyclobutane-1,2′-pyrido[3,2-b][1,4]oxazinyl,    3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl,    3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazinyl, imidazo[1,2-a]pyridinyl,    6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indolyl,    7,8,9,9a-tetrahydro-5H-pyrido[2,3-e]pyrrolo[1,2-a][1,4]diazepin-10(11H)-onyl,    indolyl, indolinyl, naphthyridinyl, pyrazolyl, pyridinyl, pyrazinyl,    pyrimidinyl, pyrrolyl, 1H-pyrrolo[2,3-b]pyridinyl, and thiazolyl,    each optionally substituted by one or more substituents    independently selected from the group consisting of oxo, alkyl,    halo, haloalkyl, cyano, N-heterocyclyl, N-heteroaryl, aryl,    —R⁸—OR^(6a), —R⁸—S(O)_(p)R^(6a) (where p is 0, 1 or 2),    —R⁸—C(O)R^(6a), —R⁸—C(O)OR^(6a), —R⁸—C(O)N(R^(6a))R^(7a),    —R⁸—N(R^(6a))R^(7a), —R⁸—N(R^(6a))—R⁹—N(R^(6a))R^(7a),    —R⁸—N(R^(6a))—R⁹—OR^(7a), —R⁸—N(R^(6a))C(O)R^(7a),    —R⁸—N(R^(6a))S(O)₂R^(7a), —R⁸—N(R^(6a))C(O)—R⁸—N(R^(6a))R^(7a), and    —R⁸—N(R^(6a))—R⁹—N(R^(6a))S(O)₂R^(7a), where the N-heterocyclyl, the    N-heteroaryl and the aryl are each independently optionally    substituted by one or more substituents selected from the group    consisting of —C(O)R⁶, —R⁸—N(R⁶)R⁷, —R⁸—C(O)N(R⁶)R⁷, alkyl, halo and    optionally substituted aryl;-   R^(5a) is selected from the group consisting of hydrogen, alkyl,    alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, optionally    substituted aryl, optionally substituted aralkyl, optionally    substituted aralkenyl, optionally substituted aralkynyl, optionally    substituted cycloalkyl, optionally substituted cycloalkylalkyl,    optionally substituted cycloalkylalkenyl, optionally substituted    cycloalkylalkynyl, optionally substituted heterocyclyl, optionally    substituted heterocyclylalkyl, optionally substituted    heterocyclylalkenyl, optionally substituted heterocyclylalkynyl,    optionally substituted heteroaryl, optionally substituted    heteroarylalkyl, optionally substituted heteroarylalkenyl,    optionally substituted heteroarylalkynyl, —R⁸—OR⁶, —R⁸—C(O)R⁶,    —R⁸—C(O)OR⁶, —R⁹—N(R⁶)R⁷, —R⁸—C(O)N(R⁶)R⁷, —R⁸—C(N═R⁶)N(R⁶)R⁷,    —R⁸—S(O)₂N(R⁶)R⁷, and —R⁸—S(O)_(t)R⁶ (where t is 1 or 2);-   each R⁶ and each R⁷ is independently selected from the group    consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl,    haloalkenyl, haloalkynyl, optionally substituted cycloalkyl,    optionally substituted cycloalkylalkyl, optionally substituted aryl,    optionally substituted aralkyl, optionally substituted aralkenyl,    optionally substituted aralkynyl, optionally substituted    heterocyclyl, optionally substituted heterocyclylalkyl, optionally    substituted heterocyclylalkenyl, optionally substituted    heterocyclylalkynyl, optionally substituted heteroaryl, optionally    substituted heteroarylalkyl, optionally substituted    heteroarylalkenyl, and optionally substituted heteroarylalkynyl; or    any R⁶ and R⁷, together with the common nitrogen to which they are    both attached, form an optionally substituted N-heteroaryl or an    optionally substituted N-heterocyclyl;-   each R^(6a) and R^(7a) is independently selected from the group    consisting of hydrogen, alkyl, optionally substituted cycloalkyl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, optionally substituted heteroaryl, and optionally    substituted aralkyl;-   each R⁸ is independently selected from the group consisting of a    direct bond and an optionally substituted straight or branched    alkylene chain; and-   each R⁹ is an optionally substituted straight or branched alkylene    chain.

Of this embodiment, one embodiment is a compound of formula (Ia-2a)wherein:

-   n is 0 or 1;-   m is 0 or 1;-   R², when present, is independently selected from the group    consisting of optionally substituted alkyl, halo, cyano and —OR⁶;-   R³, when present, is independently selected from the group    consisting of alkyl, halo and haloalkyl;-   R⁴ is pyridinyl substituted by one or more substituents selected    from the group consisting of alkyl, cyano, —R⁸—OR^(6a),    —R⁸—N(R^(6a))R^(7a), —R⁸—N(R^(6a))—R⁹—N(R^(6a))R^(7a) and    —R⁸—N(R^(6a))—R⁹—OR^(7a);-   R^(5a) is independently selected from the group consisting of    hydrogen, alkyl, —R⁸—C(O)R⁶ and —R⁸—S(O)_(t)R⁶ (where t is 1 or 2);    and-   each R⁶ is independently selected from the group consisting of    hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl,    haloalkynyl, optionally substituted cycloalkyl, optionally    substituted cycloalkylalkyl, optionally substituted aryl, optionally    substituted aralkyl, optionally substituted aralkenyl, optionally    substituted aralkynyl, optionally substituted heterocyclyl,    optionally substituted heterocyclylalkyl, optionally substituted    heterocyclylalkenyl, optionally substituted heterocyclylalkynyl,    optionally substituted heteroaryl, optionally substituted    heteroarylalkyl, optionally substituted heteroarylalkenyl, and    optionally substituted heteroarylalkynyl;-   R^(6a) and R^(7a) are each independently selected from the group    consisting of hydrogen, alkyl, optionally substituted cycloalkyl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, optionally substituted heteroaryl, and optionally    substituted aralkyl;-   each R⁸ is independently selected from the group consisting of a    direct bond and an optionally substituted straight or branched    alkylene chain; and-   each R⁹ is an optionally substituted straight or branched alkylene    chain.

A specific embodiment of this embodiment is a compound of formula(Ia-2a) selected from the group consisting of:

-   4-(6-(dimethylamino)pyridin-3-yl)-N-(6-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)pyrimidin-2-amine;-   4-(6-(dimethylamino)pyridin-3-yl)-N-(5-methyl-6-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)pyrimidin-2-amine;    and-   4-(6-aminopyridin-3-yl)-N-(5-methyl-6-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)pyrimidin-2-amine.

Another embodiment is a compound of formula (Ia-2a) wherein:

-   n is 0 or 1;-   m is 0 or 1;-   R², when present, is independently selected from the group    consisting of optionally substituted alkyl, halo, cyano and —OR⁶;-   R³, when present, is independently selected from the group    consisting of alkyl, halo and haloalkyl;-   R⁴ is pyridinyl substituted by an N-heterocyclyl selected from the    group consisting of morpholinyl, piperazinyl, piperidinyl,    oxazepanyl, 5-oxa-2-azabicyclo[2.2.1]heptanyl and thiamorpholinyl,    where the N-heterocyclyl is optionally substituted by one or more    substituents selected from the group consisting of —C(O)R⁶,    —R⁸—N(R⁶)R⁷, —R⁸—C(O)N(R⁶)R⁷, alkyl, halo and optionally substituted    aryl;-   R^(5a) is independently selected from the group consisting of    hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl,    optionally substituted cycloalkylalkyl, —R⁸—C(O)R⁶, —R⁸—C(O)N(R⁶)R⁷,    —R⁸—C(N═R⁶)N(R⁶)R⁷ and —R⁸—S(O)_(t)R⁶ (where t is 1 or 2);-   each R⁶ and each R⁷ is independently selected from the group    consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl,    haloalkenyl, haloalkynyl, optionally substituted cycloalkyl,    optionally substituted cycloalkylalkyl, optionally substituted aryl,    optionally substituted aralkyl, optionally substituted aralkenyl,    optionally substituted aralkynyl, optionally substituted    heterocyclyl, optionally substituted heterocyclylalkyl, optionally    substituted heterocyclylalkenyl, optionally substituted    heterocyclylalkynyl, optionally substituted heteroaryl, optionally    substituted heteroarylalkyl, optionally substituted    heteroarylalkenyl, and optionally substituted heteroarylalkynyl; or    any R⁶ and R⁷, together with the common nitrogen to which they are    both attached, form an optionally substituted N-heteroaryl or an    optionally substituted N-heterocyclyl; and-   each R⁸ is independently selected from the group consisting of a    direct bond and an optionally substituted straight or branched    alkylene chain.

A specific embodiment of this embodiment is a compound of formula(Ia-2a) selected from the group consisting of:

-   4-(6-(4-acetylpiperazin-1-yl)pyridin-3-yl)-N-(6-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)pyrimidin-2-amine;-   4-(5-methyl-6-(morpholin-4-yl)pyridin-3-yl)-N-(6-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)pyrimidin-2-amine;-   4-(6-(4-acetylpiperazin-1-yl)pyridin-3-yl)-N-(5-methyl-6-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)pyrimidin-2-amine;-   4-(5-methyl-6-(morpholin-4-yl)pyridin-3-yl)-N-(5-methyl-6-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)pyrimidin-2-amine;-   4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(5-methyl-6-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)pyrimidin-2-amine;-   4-(6-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)pyridin-3-yl)-N-(5-methyl-6-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)pyrimidin-2-amine.

Another embodiment is a compound of formula (Ia-2a) wherein:

-   n is 0 or 1;-   m is 0 or 1;-   R², when present, is independently selected from the group    consisting of optionally substituted alkyl, halo, cyano and —OR⁶;-   R³, when present, is independently selected from the group    consisting of alkyl, halo and haloalkyl;-   R⁴ is pyridinyl substituted by one or more substituents selected    from the group consisting of —R⁸—C(O)R^(6a),    —R⁸—C(O)N(R^(6a))R^(7a), —R⁸—S(O)_(p)R^(6a) (where p is 0, 1 or 2),    —R⁸—N(R^(6a))—R⁹—N(R^(6a))S(O)₂R^(7a), —R⁸—N(R^(6a))C(O)R^(7a),    —R⁸—N(R^(6a))S(O)₂R^(7a), —R⁸—N(R^(6a))C(O)—R⁸—N(R^(6a))R^(7a), and    tetrazolyl;-   R^(5a) is independently selected from the group consisting of    hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl,    optionally substituted cycloalkylalkyl, —R⁸—C(O)R⁶, —R⁸—C(O)N(R⁶)R⁷,    —R⁸—C(N═R⁶)N(R⁶)R⁷ and —R⁸—S(O)_(t)R⁶ (where t is 1 or 2);-   each R⁶ and each R⁷ is independently selected from the group    consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl,    haloalkenyl, haloalkynyl, optionally substituted cycloalkyl,    optionally substituted cycloalkylalkyl, optionally substituted aryl,    optionally substituted aralkyl, optionally substituted aralkenyl,    optionally substituted aralkynyl, optionally substituted    heterocyclyl, optionally substituted heterocyclylalkyl, optionally    substituted heterocyclylalkenyl, optionally substituted    heterocyclylalkynyl, optionally substituted heteroaryl, optionally    substituted heteroarylalkyl, optionally substituted    heteroarylalkenyl, and optionally substituted heteroarylalkynyl; or    any R⁶ and R⁷, together with the common nitrogen to which they are    both attached, form an optionally substituted N-heteroaryl or an    optionally substituted N-heterocyclyl;-   each R^(6a) and R^(7a) is independently selected from the group    consisting of hydrogen, alkyl, optionally substituted cycloalkyl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, optionally substituted heteroaryl, and optionally    substituted aralkyl;-   each R⁸ is independently selected from the group consisting of a    direct bond and an optionally substituted straight or branched    alkylene chain; and-   each R⁹ is an optionally substituted straight or branched alkylene    chain.

A specific embodiment of this embodiment is a compound of formula(Ia-2a) selected from the group consisting of:

-   4-(6-(methylcarbonylamino)pyridin-3-yl)-N-(6-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)pyrimidin-2-amine;-   4-(6-(2-(morpholin-4-yl)acetamido)pyridin-3-yl)-N-(5-methyl-6-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)pyrimidin-2-amine;-   4-(6-(acetamido)pyridin-3-yl)-N-(5-methyl-6-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)pyrimidin-2-amine;    and-   4-(6-(methylsulfonylamino)pyridin-3-yl)-N-(5-methyl-6-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)pyrimidin-2-amine.

Another embodiment is a compound of formula (Ia-2a) wherein:

-   n is 0 or 1;-   m is 0 or 1;-   R², when present, is independently selected from the group    consisting of optionally substituted alkyl, halo, cyano and —OR⁶;-   R³, when present, is independently selected from the group    consisting of alkyl, halo and haloalkyl;-   R⁴ is selected from the group consisting of naphthyridinyl,    benzo[b]azepinyl, benzo[b][1,4]oxazinyl,    3,4-dihydro-2H-benzo[b][1,4]thiazinyl,    3′,4′-dihydrospiro[cyclobutane-1,2′-pyrido[3,2-b][1,4]oxazinyl,    3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazinyl and    3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl, each optionally    substituted by one or more substituents independently selected from    the group consisting of alkyl and oxo;-   R^(5a) is independently selected from the group consisting of    hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl,    optionally substituted cycloalkylalkyl, —R⁸—C(O)R⁶, —R⁸—C(O)N(R⁶)R⁷,    —R⁸—C(N═R⁶)N(R⁶)R⁷, —R⁸—S(O)_(t)R⁶ (where t is 1 or 2), and    —R⁸—S(O)₂N(R⁶)R⁷;-   each R⁶ and each R⁷ is independently selected from the group    consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl,    haloalkenyl, haloalkynyl, optionally substituted cycloalkyl,    optionally substituted cycloalkylalkyl, optionally substituted aryl,    optionally substituted aralkyl, optionally substituted aralkenyl,    optionally substituted aralkynyl, optionally substituted    heterocyclyl, optionally substituted heterocyclylalkyl, optionally    substituted heterocyclylalkenyl, optionally substituted    heterocyclylalkynyl, optionally substituted heteroaryl, optionally    substituted heteroarylalkyl, optionally substituted    heteroarylalkenyl, and optionally substituted heteroarylalkynyl; or    any R⁶ and R⁷, together with the common nitrogen to which they are    both attached, form an optionally substituted N-heteroaryl or an    optionally substituted N-heterocyclyl; and-   each R⁸ is independently selected from the group consisting of a    direct bond and an optionally substituted straight or branched    alkylene chain.

A specific embodiment of this embodiment is a compound of formula(Ia-2a) selected from the group consisting of:

-   4-(4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(5-methyl-6-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)pyrimidin-2-amine;    and-   4-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(5-methyl-6-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)pyrimidin-2-amine.

Another embodiment is a compound of formula (Ia-2a) wherein:

-   n is 0 or 1;-   m is 0 or 1;-   R², when present, is independently selected from the group    consisting of optionally substituted alkyl, halo, cyano and —OR⁶;-   R³, when present, is independently selected from the group    consisting of alkyl, halo and haloalkyl;-   R⁴ is phenyl substituted by one or more substituents selected from    the group consisting of alkyl, —R⁸—OR^(6a), —R⁸—N(R^(6a))R^(7a),    —R⁸—C(O)N(R^(6a))R^(7a), —R⁸—N(R^(6a))C(O)R^(7a),    —R⁸—N(R^(6a))S(O)₂R^(7a), —R⁸—N(R^(6a))C(O)—R⁸—N(R^(6a))R^(7a),    N-heteroaryl and N-heterocyclyl, where the N-heterocyclyl and the    N-heteroaryl are each independently optionally substituted by one or    more substituents selected from the group consisting of —C(O)R⁶,    —R⁸—N(R⁶)R⁷, —R⁸—C(O)N(R⁶)R⁷, alkyl, halo and optionally substituted    aryl;-   R^(5a) is independently selected from the group consisting of    hydrogen, alkyl, —R⁸—C(O)R⁶ and —R⁸—S(O)_(t)R⁶ (where t is 1 or 2);-   each R⁶ and each R⁷ is independently selected from the group    consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl,    haloalkenyl, haloalkynyl, optionally substituted cycloalkyl,    optionally substituted cycloalkylalkyl, optionally substituted aryl,    optionally substituted aralkyl, optionally substituted aralkenyl,    optionally substituted aralkynyl, optionally substituted    heterocyclyl, optionally substituted heterocyclylalkyl, optionally    substituted heterocyclylalkenyl, optionally substituted    heterocyclylalkynyl, optionally substituted heteroaryl, optionally    substituted heteroarylalkyl, optionally substituted    heteroarylalkenyl, and optionally substituted heteroarylalkynyl; or    any R⁶ and R⁷, together with the common nitrogen to which they are    both attached, form an optionally substituted N-heteroaryl or an    optionally substituted N-heterocyclyl;-   each R^(6a) and R^(7a) is independently selected from the group    consisting of hydrogen, alkyl, optionally substituted cycloalkyl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, optionally substituted heteroaryl, and optionally    substituted aralkyl; and-   each R⁸ is independently selected from the group consisting of a    direct bond and an optionally substituted straight or branched    alkylene chain.

A specific embodiment of this embodiment is a compound of formula(Ia-2a) selected from the group consisting of:

-   4-(4-(dimethylamino)phenyl)-N-(6-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)pyrimidin-2-amine;-   4-(4-(dimethylamino)phenyl)-N-(5-methyl-6-((1S,4S)-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)pyrimidin-2-amine;-   4-(4-(t-butylcarbonylamino)phenyl)-N-(5-methyl-6-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)pyrimidin-2-amine;    and-   4-(4-(3-cyclopropylureido)phenyl)-N-(5-methyl-6-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)pyrimidin-2-amine.

Another embodiment is a compound of formula (Ia-2a) wherein:

-   n is 0 or 1;-   m is 0 or 1;-   R², when present, is independently selected from the group    consisting of optionally substituted alkyl, halo, cyano and —OR⁶;-   R³, when present, is independently selected from the group    consisting of alkyl, halo and haloalkyl;-   R⁴ is selected from the group consisting of benzimidazolyl,    imidazo[1,2-a]pyridinyl, indolyl, indolinyl, pyrazolyl, pyridinyl,    pyrazinyl, pyrimidinyl, pyrrolyl, 1H-pyrrolo[2,3-b]pyridinyl and    thiazolyl, each independently substituted by one or more    substituents selected from the group consisting of alkyl, cyano,    oxo, —R⁸—OR^(6a), —R⁸—N(R^(6a))R^(7a), —R⁸—C(O)N(R^(6a))R^(7a),    —R⁸—N(R^(6a))C(O)R^(7a), —R⁸—N(R^(6a))S(O)₂R^(7a),    —R⁸—N(R^(6a))C(O)—R⁸—N(R^(6a))R^(7a), aryl, N-heteroaryl and    N-heterocyclyl, where the aryl, the N-heterocyclyl and the    N-heteroaryl are each independently optionally substituted by one or    more substituents selected from the group consisting of —C(O)R⁶,    —R⁸—N(R⁶)R⁷, —R⁸—C(O)N(R⁶)R⁷, alkyl, halo and optionally substituted    aryl;-   R^(5a) is independently selected from the group consisting of    hydrogen, alkyl, —R⁸—C(O)R⁶ and —R⁸—S(O)_(t)R⁶ (where t is 1 or 2);-   each R⁶ and each R⁷ is independently selected from the group    consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl,    haloalkenyl, haloalkynyl, optionally substituted cycloalkyl,    optionally substituted cycloalkylalkyl, optionally substituted aryl,    optionally substituted aralkyl, optionally substituted aralkenyl,    optionally substituted aralkynyl, optionally substituted    heterocyclyl, optionally substituted heterocyclylalkyl, optionally    substituted heterocyclylalkenyl, optionally substituted    heterocyclylalkynyl, optionally substituted heteroaryl, optionally    substituted heteroarylalkyl, optionally substituted    heteroarylalkenyl, and optionally substituted heteroarylalkynyl; or    any R⁶ and R⁷, together with the common nitrogen to which they are    both attached, form an optionally substituted N-heteroaryl or an    optionally substituted N-heterocyclyl;-   each R^(6a) and R^(7a) is independently selected from the group    consisting of hydrogen, alkyl, optionally substituted cycloalkyl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, optionally substituted heteroaryl, and optionally    substituted aralkyl; and-   each R⁸ is independently selected from the group consisting of a    direct bond and an optionally substituted straight or branched    alkylene chain.

A specific embodiment of this embodiment is a compound of formula(Ia-2a) selected from the group consisting of:

-   4-(2-(dimethylamino)thiazol-4-yl)-N-(6-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)pyrimidin-2-amine;-   4-(5-(morpholin-4-yl)pyrazin-2-yl)-N-(6-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)pyrimidin-2-amine;    and-   4-(1-(pyridin-4-yl)-1H-indol-5-yl)-N-(5-methyl-6-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)pyrimidin-2-amine.

In certain embodiments of the compounds of the invention, n is 0 or 1.

In certain embodiments of the compounds of the invention, m is 0 or 1.

In certain embodiments of the compounds of the invention, Y is ═C(R⁶)—.

In certain embodiments of the compounds of the invention Y is ═N—.

In certain embodiments of the compounds of the invention, R¹ is selectedfrom the group consisting of hydrogen, alkyl, haloalkyl, optionallysubstituted cycloalkyl, optionally substituted cycloalkylalkyl,optionally substituted aryl, optionally substituted aralkyl,—R⁸—C(O)OR⁶, —R⁹—N(R⁶)R⁷ and —R⁹—OR⁶;

In certain embodiments of the compounds of the invention, R⁵ is anN-heterocyclyl, wherein a nitrogen atom in the N-heterocyclyl isoptionally substituted by a substituent selected from the groupconsisting of alkyl, haloalkyl, optionally substituted aryl, optionallysubstituted aralkyl, optionally substituted cycloalkyl, optionallysubstituted cycloalkylalkyl, optionally substituted heterocyclyl,optionally substituted heterocyclylalkyl, optionally substitutedheteroaryl, optionally substituted heteroarylalkyl, —R⁸—OR⁶, —R⁸—C(O)R⁶,—R⁸—C(O)OR⁶, —R⁹—N(R⁶)R⁷, —R⁸—C(O)N(R⁶)R⁷, —R⁸—C(N═R⁶)N(R⁶)R⁷,—R⁸—S(O)₂N(R⁶)R⁷, and —R⁸—S(O)_(t)R⁶ (where t is 1 or 2); and a carbonatom in the N-heterocyclyl is optionally substituted by a substituentselected from the group consisting of alkyl, halo, haloalkyl, optionallysubstituted aryl, optionally substituted aralkyl, optionally substitutedcycloalkyl, optionally substituted cycloalkylalkyl, optionallysubstituted heterocyclyl, optionally substituted heterocyclylalkyl,optionally substituted heteroaryl, optionally substitutedheteroarylalkyl, —R⁸—OR⁶, —R⁸—C(O)R⁶, —R⁸—C(O)OR⁶, —R⁹—N(R⁶)R⁷,—R⁸—C(O)N(R⁶)R⁷, —R⁸—S(O)₂N(R⁶)R⁷, and —R⁸—S(O)_(p)R⁶ (where p is 0, 1or 2).

In certain embodiments of the compounds of the invention, each R⁶ andeach R⁷ is independently selected from the group consisting of hydrogen,alkyl, haloalkyl, haloalkenyl, optionally substituted cycloalkyl,optionally substituted cycloalkylalkyl, optionally substituted aryl,optionally substituted aralkyl, optionally substituted heterocyclyl,optionally substituted heterocyclylalkyl, optionally substitutedheteroaryl, optionally substituted heteroarylalkyl.

In one embodiment, the compounds of formula (I) are selected from thegroup consisting of:

-   4-(6-(N,N-dimethylamino)pyridin-3-yl)-N-(3-methyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(N,N-dimethylamino)pyridin-3-yl)-5-methyl-N-(3-methyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(N,N-dimethylamino)pyridin-3-yl)-5-trifluoromethyl-N-(3-methyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(N,N-dimethylamino)pyridin-3-yl)-5-fluoro-N-(3-methyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(N,N-dimethylamino)pyridin-3-yl)-5-fluoro-N-(3-fluoro-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(N,N-dimethylamino)pyridin-3-yl)-5-methyl-N-(3-fluoro-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(N,N-dimethylamino)pyridin-3-yl)-N-(3-fluoro-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(3-methyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(3-fluoro-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-methyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-fluoro-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)-N-(3-methyl-4-(4-methylpiperazin-1-yl)phenyl)pyrimidin-2-amine;-   4-(6-(5-(4-fluorophenyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)-N-(3-methyl-4-(4-methylpiperazin-1-yl)phenyl)pyrimidin-2-amine;-   4-(4-(N,N-dimethylamino)phenyl)-N-(3-methyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(4-(N,N-dimethylamino)phenyl)-N-(3-fluoro-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(4-acetylpiperazin-1-yl)pyridin-3-yl)-N-(3-fluoro-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(3-fluoro-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(3-methyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(1H-indol-6-yl)-N-(3-methyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(1H-pyrrolo[2,3-b]pyridin-5-yl)-N-(3-methyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(1H-pyrrolo[2,3-b]pyridin-5-yl)-N-(3-fluoro-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(dimethylamino)pyridin-3-yl)-N-(3-methyl-4-(5-ethyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-methyl-4-(5-ethyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-methyl-4-(5-((ethylamino)carbonyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(3-methyl-4-(5-oxa-2-azabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(3-methyl-4-(5-(ethylcarbonyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(3-methyl-4-(5-(methylsulfonyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(3-methyl-4-(5-ethyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(3′-oxo-3,4′-dihydrospiro[cyclobutane-1,2′-pyrido[3,2-b][1,4]oxazine]-7-yl)-N-(3-methyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(3-oxo-3,4′-dihydrospiro[cyclobutane-1,2′-pyrido[3,2-b][1,4]oxazine]-7-yl)-N-(3-methyl-4-(5-ethyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(1H-pyrrolo[2,3-b]pyridin-5-yl)-N-(3-methyl-4-(5-oxa-2-azabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(1H-pyrrolo[2,3-b]pyridin-5-yl)-N-(3-methyl-4-(5-(2,2,2-trifluoroethyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(1H-pyrrolo[2,3-b]pyridin-5-yl)-N-(3-methyl-4-(5-(cyclopropyl)methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-methyl-4-(5-(2,2,2-trifluoroethyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-methyl-4-(5-(cyclopropyl)methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(3-methyl-4-(5-(aminosulfonyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(3-fluoro-2-(morpholin-4-yl)pyridin-4-yl)-N-(3-fluoro-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(2-(morpholin-4-yl)pyrimidin-5-yl)-N-(4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(2-(morpholin-4-yl)pyrimidin-5-yl)-N-(3-methyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(2-(morpholin-4-yl)pyrimidin-5-yl)-N-(3-methyl-4-(5-oxa-2-azabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(2-(morpholin-4-yl)pyrimidin-5-yl)-N-(3-fluoro-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(2-((cyclopropyl)carbonylamino)-pyrimidin-5-yl)-N-(3-methyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(4-(4,5-dihydrothiazol-2-ylcarbamoyl)phenyl)-N-(3-methyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(4-(1,1-dimethylethyl)phenyl)-N-(3-methyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(4-(morpholin-4-yl)phenyl)-N-(3-fluoro-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine.TFA    salt;-   4-(4-((methyl)aminocarbonylmethyl)-phenyl)-N-(3-methyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine.TFA    salt;-   4-(4-((cyclopropyl)aminocarbonyl-methyl)phenyl)-N-(3-methyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(methylaminocarbonyl)pyridin-3-yl)-N-(3-methyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)-N-(3-methyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine.TFA    salt;-   4-(5-((morpholin-4-yl)carbonyl)pyridin-3-yl)-N-(3-methyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine.Bis    TFA salt;-   4-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(3-cyano-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(5-methyl-6-(morpholin-4-yl)pyridin-3-yl)-N-(3-fluoro-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(5-methyl-6-(morpholin-4-yl)pyridin-3-yl)-N-(3-methyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   5-methyl-4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-methyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   5-methyl-4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-fluoro-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(2-(morpholin-4-yl)ethyl)aminopyridin-3-yl)-N-(4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(2-(morpholin-4-yl)ethyl)aminopyridin-3-yl)-N-(3-fluoro-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(3-methyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-methyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(3-fluoro-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-fluoro-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-methyl-4-(1,5,7-trimethyl-3,7-diazabicyclo[3.3.1]nonan-3-yl)phenyl)pyrimidin-2-amine;-   4-(6-(dimethylamino)pyridin-3-yl)-N-(3-methyl-4-(1,5,7-trimethyl-3,7-diazabicyclo[3.3.1]nonan-3-yl)phenyl)pyrimidin-2-amine;-   4-(6-(cyclohexylamino)pyridin-3-yl)-N-(3-methyl-4-(1,5,7-trimethyl-3,7-diazabicyclo[3.3.1]nonan-3-yl)phenyl)pyrimidin-2-amine;-   4-(6-(cyclohexylamino)pyridin-3-yl)-N-(3-methyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(cyclohexylamino)pyridin-3-yl)-N-(3-fluoro-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(benzyl)pyridin-3-yl)-N-(3-methyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(benzyl)pyridin-3-yl)-N-(3-fluoro-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(5-methyl-6-(morpholin-4-yl)pyridin-3-yl)-N-(3-fluoro-4-(1,5,7-trimethyl-3,7-diazabicyclo[3.3.1]nonan-3-yl)phenyl)pyrimidin-2-amine;-   4-(6-(dimethylamino)pyridin-3-yl)-N-(3-fluoro-4-(1,5,7-trimethyl-3,7-diazabicyclo[3.3.1]nonan-3-yl)phenyl)pyrimidin-2-amine;-   4-(4-(dimethylamino)phenyl)-N-(3-fluoro-4-(1,5,7-trimethyl-3,7-diazabicyclo[3.3.1]nonan-3-yl)phenyl)pyrimidin-2-amine;-   4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-fluoro-4-(1,5,7-trimethyl-3,7-diazabicyclo[3.3.1]nonan-3-yl)phenyl)pyrimidin-2-amine;-   4-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(3-methyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(3-fluoro-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(3-methyl-4-(1,5,7-trimethyl-3,7-diazabicyclo[3.3.1]nonan-3-yl)phenyl)pyrimidin-2-amine;-   4-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(3-fluoro-4-(1,5,7-trimethyl-3,7-diazabicyclo[3.3.1]nonan-3-yl)phenyl)pyrimidin-2-amine;-   4-(6-(benzyl)pyridin-3-yl)-N-(3-methyl-4-(1,5,7-trimethyl-3,7-diazabicyclo[3.3.1]nonan-3-yl)phenyl)pyrimidin-2-amine;-   4-(6-(benzyl)pyridin-3-yl)-N-(3-fluoro-4-(1,5,7-trimethyl-3,7-diazabicyclo[3.3.1]nonan-3-yl)phenyl)pyrimidin-2-amine;-   4-(2-(propyl)aminopyrimidin-5-yl)-N-(3-methyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(2-(propyl)aminopyrimidin-5-yl)-N-(3-fluoro-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(cyclohexylamino)pyridin-3-yl)-N-(3-trifluoromethyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(5-(methyl)sulfonylpyridin-3-yl)-N-(3-methyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(dimethylamino)pyridin-3-yl)-N-(3-trifluoromethyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-trifluoromethyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(3-trifluoromethyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-((2-(cyclopropylsulfonyl)aminoethyl)-amino)pyridin-3-yl)-N-(3-methyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-((2-(cyclopropylsulfonyl)aminoethyl)-amino)pyridin-3-yl)-N-(3-methyl-4-(5-oxa-2-azabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(5-(methyl)sulfonylpyridin-3-yl)-N-(3-fluoro-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(5-(methyl)sulfonylpyridin-3-yl)-N-(3-trifluoromethyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(imidazo[1,2-a]pyridin-6-yl)-N-(3-methyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(4-(5-(4-dimethylaminophenyl)oxazol-2-yl)phenyl)-N-(3-methyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-methoxy-1H-indol-2-yl)-N-(3-methyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(1-(3-chlorophenyl)-1H-pyrazol-4-yl)-N-(3-methyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(1-methylbenzimidazol-6-yl)-N-(3-methyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(5-cyano-1H-indol-2-yl)-N-(3-methyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)-N-(3-methyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-methyl-4-(7-azabicyclo[2.2.1]heptan-7-yl)phenyl)pyrimidin-2-amine;-   4-(6-cyanopyridin-3-yl)-N-(3-methyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-cyanopyridin-3-yl)-N-(3-methyl-4-(7-azabicyclo[2.2.1]heptan-7-yl)phenyl)pyrimidin-2-amine;-   4-(2-oxoindolin-5-yl)-N-(3-methyl-4(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(5-cyanopyridin-3-yl)-N-(3-methyl-4(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(1H-tetrazol-5-yl)pyridin-3-yl)-N-(3-methyl-4(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-cyano-4-(5-acetyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-cyano-4-(5-methylsulfonyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-cyano-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-cyano-4-(5-cyclopentyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-methyl-4-(1,4-diazabicyclo[3.2.1]octan-4-yl)phenyl)pyrimidin-2-amine;-   4-(2-oxoindolin-5-yl)-N-(3-methyl-4-(1,4-diazabicyclo[3.2.1]octan-4-yl)phenyl)pyrimidin-2-amine;-   (1-methylbenzimidazol-6-yl)-N-(3-methyl-4-(1,4-diazabicyclo[3.2.1]octan-4-yl)phenyl)pyrimidin-2-amine;-   4-(imidazo[1,2-a]pyridin-6-yl)-N-(3-methyl-4-(1,4-diazabicyclo[3.2.1]octan-4-yl)phenyl)pyrimidin-2-amine;-   4-(2H-benzo[b][1,4]oxazin-3(4H)-on-6-yl)-N-(3-fluoro-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(2,2,4-trimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(3-methyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(2,2,4-trimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(3-fluoro-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(5-(3-methylpiperidin-1-yl)pyrazin-2-yl)-N-(3-fluoro-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(4-(t-butylcarbonylamino)phenyl)-N-(3-fluoro-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(4-(t-butylcarbonylamino)phenyl)-N-(3-methyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(3-methyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(acetamido)pyridin-3-yl)-N-(3-methyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(4-((pyridin-2-yl)aminocarbonyl)phenyl)-N-(3-fluoro-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(4-((pyridin-2-yl)aminocarbonyl)phenyl)-N-(3-methyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(4-(methylsulfonylamino)phenyl)-N-(3-fluoro-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(4-(methylsulfonylamino)phenyl)-N-(3-methyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(4-(3-cyclopropylureido)phenyl)-N-(4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(2-(morpholin-4-yl)acetamido)pyridin-3-yl)-N-(3-methyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(2-(morpholin-4-yl)acetamido)pyridin-3-yl)-N-(4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(2-(morpholin-4-yl)acetamido)pyridin-3-yl)-N-(3-fluoro-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(acetamido)pyridin-3-yl)-N-(3-methyl-4-(5-oxa-2-azabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-aminopyridin-3-yl)-N-(3-methyl-4-(5-ethylcarbonyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(acetamido)pyridin-3-yl)-N-(3-methyl-4-(5-ethylcarbonyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-aminopyridin-3-yl)-N-(3-methyl-4-(5-methylsulfonyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(methylsulfonylamino)pyridin-3-yl)-N-(3-methyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(2-(dimethylamino)acetamido)-pyridin-3-yl)-N-(3-methyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(methylsulfonylamino)pyridin-3-yl)-N-(3-fluoro-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(4-(8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)pyrimidin-2-amine;-   4-(6-(methylsulfonylamino)pyridin-3-yl)-N-(4-(8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)pyrimidin-2-amine;-   4-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(4-(8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)pyrimidin-2-amine;-   4-(6-aminopyridin-3-yl)-N-(4-(8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)pyrimidin-2-amine;-   4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-methyl-4-(1,4-diazabicyclo[3.2.2]nonan-4-yl)phenyl)pyrimidin-2-amine;-   4-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(3-methyl-4-(1,4-diazabicyclo[3.2.2]nonan-4-yl)phenyl)pyrimidin-2-amine;-   4-(4-((pyridin-2-yl)aminocarbonyl)phenyl)-N-(3-methyl-4-(1,4-diazabicyclo[3.2.2]nonan-4-yl)phenyl)pyrimidin-2-amine;-   4-(4-(acetamido)phenyl)-N-(4-(8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)pyrimidin-2-amine;-   4-(2-(diethylamino)thiazol-4-yl)-N-(3-methyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(2-(diethylamino)thiazol-4-yl)-N-(3-fluoro-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(3-methyl-4-(8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)pyrimidin-2-amine;-   4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-methyl-4-(8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)pyrimidin-2-amine;-   4-(6-(methylsulfonylamino)pyridin-3-yl)-N-(3-methyl-4-(8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)pyrimidin-2-amine;-   4-(4-(t-butylcarbonylamino)phenyl)-N-(3-methyl-4-(8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)pyrimidin-2-amine;-   4-(1H-pyrrol-3-yl)-N-(3-methyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(1H-pyrrol-3-yl)-N-(4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(1H-pyrrol-3-yl)-N-(3-trifluoromethyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(3-trifluoromethyl-4-(2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-ethoxypyridin-3-yl)-N-(3-methyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-ethoxypyridin-3-yl)-N-(3-fluoro-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(2-(dimethylamino)thiazol-4-yl)-N-(3-methyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(2-(dimethylamino)thiazol-4-yl)-N-(3-fluoro-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(5-(morpholin-4-yl)pyrazin-2-yl)-N-(3-methyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(5-(morpholin-4-yl)pyrazin-2-yl)-N-(3-fluoro-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(4-(1-ethoxyethyl)phenyl)-N-(3-methyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(4-(1-ethoxyethyl)phenyl)-N-(3-fluoro-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(dimethylamino)pyridin-3-yl)-N-(4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(3-ethoxypropyl)aminopyridin-3-yl)-N-(3-methyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(cis-2,6-dimethylmorpholin-4-yl)pyridin-3-yl)-N-(3-methyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(propylamino)pyridin-3-yl)-N-(3-methyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(2-(dimethylamino)methylmorpholin-4-yl)pyridin-3-yl)-N-(3-methyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(piperidin-1-yl)pyridin-3-yl)-N-(3-methyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(3-(aminocarbonyl)piperidin-1-yl)pyridin-3-yl)-N-(3-methyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-methyl-4-(5-methylsulfonyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(3-methyl-4-(5-methylsulfonyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-methyl-4-(5-oxa-2-azabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(3-methyl-4-(5-oxa-2-azabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-methyl-4-(5-ethylcarbonyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(2-(morpholin-4-yl)ethyl)aminopyridin-3-yl)-N-(3-methyl-4-(5-ethylcarbonyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(3-dimethylamino)propylaminopyridin-3-yl)-N-(3-methyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-methyl-4-(5-amidino-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine.    TFA salt;-   4-(6-(3-ethoxypropyl)aminopyridin-3-yl)-N-(3-methyl-4-(5-oxa-2-azabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-cis-2,6-dimethylmorpholin-4-yl)pyridin-3-yl)-N-(3-methyl-4-(5-oxa-2-azabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(propylamino)pyridin-3-yl)-N-(3-methyl-4-(5-oxa-2-azabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(3-dimethylamino)propylaminopyridin-3-yl)-N-(3-methyl-4-(5-oxa-2-azabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(1,4-oxazepan-4-yl)pyridin-3-yl)-N-(3-methyl-4-(5-oxa-2-azabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-methyl-4-(5-isobutyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(1,4-oxazepan-4-yl)pyridin-3-yl)-N-(3-methyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(3-methyl-4-(1,5,7-trimethyl-3,7-diazabicyclo[3.3.1]nonan-3-yl)phenyl)pyrimidin-2-amine;-   4-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(3-fluoro-4-(1,5,7-trimethyl-3,7-diazabicyclo[3.3.1]nonan-3-yl)phenyl)pyrimidin-2-amine;-   4-(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(3-methyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(3-methyl-4-(5-oxa-2-azabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(3-ethoxypropyl)aminopyridin-3-yl)-N-(3-methyl-4-(1,5,7-trimethyl-3,7-diazabicyclo[3.3.1]nonan-3-yl)phenyl)pyrimidin-2-amine;-   4-(6-((2S,6R)-2,6-dimethylmorpholin-4-yl)pyridin-3-yl)-N-(3-methyl-4-(1,5,7-trimethyl-3,7-diazabicyclo[3.3.1]nonan-3-yl)phenyl)pyrimidin-2-amine;-   4-(6-(propylamino)pyridin-3-yl)-N-(3-methyl-4-(1,5,7-trimethyl-3,7-diazabicyclo[3.3.1]nonan-3-yl)phenyl)pyrimidin-2-amine;-   4-(6-(3-dimethylamino)propylaminopyridin-3-yl)-N-(3-methyl-4-(1,5,7-trimethyl-3,7-diazabicyclo[3.3.1]nonan-3-yl)phenyl)pyrimidin-2-amine;-   4-(6-(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)pyridin-3-yl)-N-(3-methyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(5-oxa-2-azabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)-N-(3-methyl-4-(5-oxa-2-azabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(3-methylbutyl)aminopyridin-3-yl)-N-(3-methyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(3,3-dimethylbutyl)aminopyridin-3-yl)-N-(3-methyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(2-methoxyethyl)(methyl)aminopyridin-3-yl)-N-(3-methyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(2-methoxyethyl)(methyl)aminopyridin-3-yl)-N-(3-methyl-4-(5-oxa-2-azabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(2-methoxyethyl)(methyl)aminopyridin-3-yl)-N-(3-methyl-4-(1,5,7-trimethyl-3,7-diazabicyclo[3.3.1]nonan-3-yl)phenyl)pyrimidin-2-amine;-   4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-methyl-4-(2-azabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(3-methyl-4-(2-azabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(3-methyl-4-(2-methylsulfonyl-2-azabicyclo[2.2.1]heptan-5-yl)phenyl)pyrimidin-2-amine    and    4-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(3-methyl-4-(2-methylsulfonyl-2-azabicyclo[2.2.1]heptan-6-yl)phenyl)pyrimidin-2-amine    (68:31);-   4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-methyl-4-(2-methylsulfonyl-2-azabicyclo[2.2.1]heptan-5-yl)phenyl)pyrimidin-2-amine    and    4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-methyl-4-(2-methylsulfonyl-2-azabicyclo[2.2.1]heptan-6-yl)phenyl)pyrimidin-2-amine    (85:15);-   4-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(4-(2-methylsulfonyl-2-azabicyclo[2.2.1]heptan-5-yl)phenyl)pyrimidin-2-amine;-   4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(4-(2-methylsulfonyl-2-azabicyclo[2.2.1]heptan-5-yl)phenyl)pyrimidin-2-amine;-   4-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(4-(2-methylsulfonyl-2-azabicyclo[2.2.1]heptan-6-yl)phenyl)pyrimidin-2-amine;-   4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(4-(2-methylsulfonyl-2-azabicyclo[2.2.1]heptan-6-yl)phenyl)pyrimidin-2-amine;-   4-(6-(thiamorpholin-4-yl)pyridin-3-yl)-N-(3-methyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-methyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(1-(pyridin-4-yl)-1H-indol-5-yl)-N-(3-methyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(1-(pyridin-4-yl)-1H-indol-5-yl)-N-(3-fluoro-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(1-(pyridin-4-yl)-1H-indol-5-yl)-N-(3-methyl-4-(5-ethyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(1-(pyridin-4-yl)-1H-indol-5-yl)-N-(3-methyl-4-(5-isobutyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)-N-(3-methyl-4-(5-methylsulfonyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(propylamino)pyridin-3-yl)-N-(3-methyl-4-(5-methylsulfonyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-7-yl)-N-(4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-N-(3-methyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-N-(3-methyl-4-(5-methylsulfonyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-yl)-N-(3-methyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-yl)-N-(3-methyl-4-(5-methylsulfonyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-N-(3-methyl-4-(6,9-methanooctahydro-1H-pyrido[1,2-a]pyrazin-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-methyl-4-(6,9-methanooctahydro-1H-pyrido[1,2-a]pyrazin-2-yl)phenyl)pyrimidin-2-amine;-   4-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(3-methyl-4-(5-(1-methylethyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(3-methyl-4-(5-cyclopropyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(3-chloro-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(3-chloro-4-(5-(methylsulfonyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(3-methyl-4-(5-cyclopentyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(3-methyl-4-(5-acetyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(3-methyl-4-(1,4-diazabicyclo[3.2.1]octan-4-yl)phenyl)pyrimidin-2-amine;-   4-(5-(1-methylethoxy)carbonylpropyl-6-aminopyridin-3-yl)-N-(3-methyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-methyl-4-(5-cyclopropyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-chloro-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(2-(trifluoromethyl)pyridin-4-yl)-N-(3-methyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-chloro-4-(5-(methylsulfonyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(tetrahydropyran-4-yloxy)pyridin-3-yl)-N-(3-chloro-4-(5-(methylsulfonyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-chloro-4-(5-acetyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(tetrahydropyran-4-yloxy)pyridin-3-yl)-N-(3-chloro-4-(5-acetyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(tetrahydropyran-4-yloxy)pyridin-3-yl)-N-(3-methyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(tetrahydropyran-4-yloxy)pyridin-3-yl)-N-(3-methyl-4-(5-cyclopentyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-chloro-4-(5-(1-methylethyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)pyridin-3-yl)-N-(3-methyl-4-(5-(methylsulfonyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-3-yl)-N-(3-methyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-3-yl)-N-(3-methyl-4-(5-(methylsulfonyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(4-(trifluoromethyl)phenyl)-N-(3-methyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(7,8,9,9a-tetrahydro-5H-pyrido[2,3-e]pyrrolo[1,2-b][1,4]diazepin-10(11H)-on-3-yl)-N-(3-methyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-N-(3-cyano-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-yl)-N-(3-cyano-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-7-yl)-N-(3-cyano-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-7-yl)-N-(3-methyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(tetrahydropyran-4-yloxy)pyridin-3-yl)-N-(3-methyl-4-(1,4-diazabicyclo[3.2.1]octan-4-yl)phenyl)pyrimidin-2-amine;-   4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-methyl-4-(1,4-diazabicyclo[3.2.1]octan-4-yl)phenyl)pyrimidin-2-amine;-   4-(2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-yl)-N-(3-methyl-4-(6,9-methanooctahydro-1H-pyrido[1,2-a]pyrazin-2-yl)phenyl)pyrimidin-2-amine;-   4-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-7-yl)-N-(3-methyl-4-(6,9-methanooctahydro-1H-pyrido[1,2-a]pyrazin-2-yl)phenyl)pyrimidin-2-amine;-   4-(6-(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)pyridin-3-yl)-N-(3-methyl-4-(1,4-diazabicyclo[3.2.2]nonan-4-yl)phenyl)pyrimidin-2-amine;-   4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-cyano-4-(3,9-diazabicyclo[3.3.2]decan-10-on-3-yl)phenyl)pyrimidin-2-amine;-   4-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(3-cyano-4-(3,9-diazabicyclo[3.3.2]decan-10-on-3-yl)phenyl)pyrimidin-2-amine;-   4-(6-(tetrahydropyran-4-yloxy)pyridin-3-yl)-N-(3-methyl-4-(3-(dimethylamino)-8-azabicyclo[3.2.1]octan-8-yl)phenyl)pyrimidin-2-amine;-   4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-methyl-4-(3-(morpholin-4-yl)-8-azabicyclo[3.2.1]octan-8-yl)phenyl)pyrimidin-2-amine;-   4-(6-(tetrahydropyran-4-yloxy)pyridin-3-yl)-N-(3-methyl-4-(3-(morpholin-4-yl)-8-azabicyclo[3.2.1]octan-8-yl)phenyl)pyrimidin-2-amine;-   4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-methyl-4-(3-(dimethylamino)-8-azabicyclo[3.2.1]octan-8-yl)phenyl)pyrimidin-2-amine;-   4-(6-(dimethylamino)pyridin-3-yl)-N-(6-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)pyrimidin-2-amine;-   4-(6-(methylcarbonylamino)pyridin-3-yl)-N-(4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)pyrimidin-2-amine;-   4-(4-(dimethylamino)phenyl)-N-(6-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)pyrimidin-2-amine;-   4-(6-(4-acetylpiperazin-1-yl)pyridin-3-yl)-N-(6-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)pyrimidin-2-amine;-   4-(5-methyl-6-(morpholin-4-yl)pyridin-3-yl)-N-(6-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)pyrimidin-2-amine;-   4-(6-(dimethylamino)pyridin-3-yl)-N-(5-methyl-6-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)pyrimidin-2-amine;-   4-(4-(dimethylamino)phenyl)-N-(5-methyl-6-((5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)pyrimidin-2-amine;-   4-(6-(4-acetylpiperazin-1-yl)pyridin-3-yl)-N-(5-methyl-6-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)pyrimidin-2-amine;-   4-(5-methyl-6-(morpholin-4-yl)pyridin-3-yl)-N-(5-methyl-6-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)pyrimidin-2-amine;-   4-(4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(5-methyl-6-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)pyrimidin-2-amine;-   4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(5-methyl-6-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)pyrimidin-2-amine;-   4-(4-(t-butylcarbonylamino)phenyl)-N-(5-methyl-6-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)pyrimidin-2-amine;-   4-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(5-methyl-6-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)pyrimidin-2-amine;-   4-(4-(3-cyclopropylureido)phenyl)-N-(5-methyl-6-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)pyrimidin-2-amine;-   4-(6-(2-(morpholin-4-yl)acetamido)pyridin-3-yl)-N-(5-methyl-6-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)pyrimidin-2-amine;-   4-(6-aminopyridin-3-yl)-N-(5-methyl-6-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)pyrimidin-2-amine;-   4-(6-(acetamido)pyridin-3-yl)-N-(5-methyl-6-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)pyrimidin-2-amine;-   4-(6-(methylsulfonylamino)pyridin-3-yl)-N-(5-methyl-6-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)pyrimidin-2-amine;-   4-(2-(dimethylamino)thiazol-4-yl)-N-(6-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)pyrimidin-2-amine;-   4-(5-(morpholin-4-yl)pyrazin-2-yl)-N-(6-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)pyrimidin-2-amine;-   4-(1-(pyridin-4-yl)-1H-indol-5-yl)-N-(5-methyl-6-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)pyrimidin-2-amine;    and-   4-(6-(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)pyridin-3-yl)-N-(5-methyl-6-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)pyrimidin-2-amine.

It is understood that the various embodiments of the compounds of theinvention, as set forth above, do not encompass compounds which arespecifically disclosed in prior publications, including scientificjournals, patents and published patent applications.

Another aspect of the invention are pharmaceutical compositionscomprising a pharmaceutically acceptable excipient and a therapeuticallyeffective amount of a compound of the invention, as set forth above inthe Summary of the Invention, as an isolated stereoisomer or a mixturethereof, or as a pharmaceutically acceptable salt thereof. Inparticular, some embodiments of the pharmaceutical compositions of theinvention comprise a pharmaceutically acceptable excipient and atherapeutically effective amount of an embodiment of a compound offormula (I), as set forth above. More specific embodiments arepharmaceutical compositions comprising a pharmaceutically acceptableexcipient and a therapeutically effective amount of a compound offormula (Ia), as set forth above.

Another aspect of the invention are methods of treating diseases orconditions associated with JAK2 activity in a mammal utilizing thecompounds and the pharmaceutical compositions of the invention. Oneembodiment of the methods of the invention disclosed herein is theadministration of a therapeutically effective amount of a compound offormula (Ia), as set forth above, to a mammal, preferably a human, inneed thereof. Another embodiment of the methods of the inventiondisclosed herein are methods of treating the diseases or conditionsassociated with JAK2 activity in a mammal wherein the disease orconditions is leukemia, lymphoma, multiple myeloma, transplantrejection, bone marrow transplant applications, autoimmune diseases,inflammation, myeloproliferative disorders, polycythemia vera disorder,essential thrombocythemia disorder and primary myelofibrosis.

It is understood that any embodiment of the compounds of the invention,as set forth above, and any specific substituent set forth herein for aparticular n, m, R¹, R², R³, R⁴, R⁵ or Y in the compounds of theinvention, as set forth above, may be independently combined with otherembodiments and/or substituents of compounds of the invention to formembodiments of the inventions not specifically set forth above. Inaddition, in the event that a list of substituents is listed for anyparticular R group or Y in a particular embodiment and/or claim, it isunderstood that each individual substituent may be deleted from theparticular embodiment and/or claim and that the remaining list ofsubstituents will be considered to be within the scope of the invention.

Specific embodiments of the invention are described in more detail belowin the following sections.

UTILITY AND TESTING OF THE COMPOUNDS OF THE INVENTION

The present invention provides pyrimidine-2-amine compounds orpharmaceutically acceptable salts thereof, as described above in theSummary of the Invention, for use in treating the diseases or conditionsas described herein. The present invention further provides use of thecompounds of the present invention in the manufacture of a medicamentfor the treatment of diseases or conditions in which targeting of theJAK pathway or inhibition of JAK kinases, particularly JAK2, can betherapeutically useful. These include diseases or conditions where thefunction of lymphocytes, macrophages, or mast cells is involved.Accordingly, diseases or conditions associated with JAK2 activity, inparticular, are diseases or conditions in which targeting of the JAKpathway or inhibition of the JAK kinases, particularly JAK2, can betherapeutically useful include, but are not limited to, leukemia,lymphoma, multiple myeloma, transplant rejection (e.g. pancreas islettransplant rejection), bone marrow transplant conditions (e.g.,graft-versus-host disease), autoimmune diseases (e.g., rheumatoidarthritis), inflammation (e.g., asthma, etc.), myeloproliferativedisorders (MPD) (e.g., polycythemia vera (PV), essential thrombocythemia(ET) and primary myelofibrosis (PMF)), and other diseases or conditionsas described in greater detail herein or which are known to one skilledin the art as being associated with JAK2 activity.

As noted previously, numerous diseases or conditions can be treatedusing the compounds of the invention, or pharmaceutically acceptablesalts thereof, and pharmaceutically compositions comprising thecompounds or pharmaceutically acceptable salts thereof. As wellunderstood in the art, “treatment” is an approach for obtainingbeneficial or desired results, including clinical results. For thepurposes of this invention, beneficial or desired results can includeone or more, but are not limited to: alleviation or amelioration of oneor more symptoms; diminishment of extent of a condition, including adisease; stabilization (i.e., not worsening) of the state of acondition, including diseases; preventing spread of disease; delay orslowing of a condition, including disease progression; amelioration orpalliation of the condition, including disease state; and remission(whether partial or total); in each case whether detectable orundetectable. Preferred are compounds that are potent and can beadministered locally at very low doses, thus minimizing systemic adverseeffects.

The compounds of the invention, or pharmaceutically acceptable saltsthereof, described herein are potent and selective inhibitors of JAKkinases, and particularly selective for cytokine signaling pathwayscontaining JAK2. As a consequence of this activity, the compounds can beused in a variety of in vitro, in vivo and ex vivo contexts to regulateor inhibit JAK kinase activity, signaling cascades in which JAK kinasesplay a role, and the biological responses effected by such signalingcascades. For example, in one embodiment, the compounds can be used toinhibit JAK kinase, either in vitro or in vivo, in virtually any celltype expressing the JAK kinase.

In hematopoietic cells in which a JAK kinase is expressed, the compoundsof the invention may be used to regulate signal transduction cascades inwhich the JAK kinase, particularly JAK2, plays a role. SuchJAK-dependent signal transduction cascades include, but are not limitedto, the signaling cascades of a wide range of cytokine receptors,including those activated by growth hormone, erythropoietin, prolactin,granulocyte colony stimulating factor (G-CSF), macrophagecolony-stimulating factor, ciliary neurotrophic factor, leukemiainhibitory factor, oncostatin M, interferon-γ, thrombopoietin, leptin,IL-3, IL-5, IL-6, IL-11, IL-12 and some G-protein-coupled (GPCR)receptor signaling cascades (angiotensin II, bradykinin, endothelin,platelet activating factor, α-melanocyte stimulating hormone,isoproterenol, and phenylephrine). The compounds may also be used invitro or in vivo to regulate, and in particular inhibit, cellular orbiological responses affected by such JAK-dependent signal transductioncascades. Such cellular or biological responses include, but are notlimited to, MAPK and AKT pathway activation, IL-3 mediated cellproliferation, etc.

Importantly, the compounds can be used to inhibit JAK kinases in vivo asa therapeutic approach towards the treatment or prevention of diseasesor conditions mediated, either wholly or in part, by a JAK kinaseactivity (referred to herein as “JAK kinase mediated diseases orconditions”). Non-limiting examples of JAK kinase mediated diseases orconditions that can be treated or prevented with the compounds of theinvention, or pharmaceutically acceptable salts thereof, include, butare not limited to: allergies; asthma; autoimmune diseases such astransplant rejection (e.g., kidney, heart, lung, liver, pancreas, skin;host versus graft reaction (HVGR), graft versus host reaction (GVHR)etc.), rheumatoid arthritis, and amyotrophic lateral sclerosis; T-cellmediated autoimmune diseases such as multiple sclerosis, psoriasis andSjogren's syndrome; Type II inflammatory diseases such as vascularinflammation (including vasculitis, arteritis, atherosclerosis andcoronary artery disease); diseases of the central nervous system such asstroke; pulmonary diseases such as bronchitis obliteraus, primarypulmonary hypertension and pulmonary arterial hypertension, and solid,delayed Type IV hypersensitivity reactions; and hematologic malignanciessuch as leukemia and lymphomas. The compounds of the invention may alsobe used for treatment of obesity, since in obese animals, JAK2/STAT andMAP kinase pathways are hyperactivated in response to insulin.

This invention also provides a method of inhibiting an activity of a JAKkinase, comprising contacting the JAK kinase with an amount of acompound effective to inhibit an activity of the JAK kinase wherein thecompound is selected from the compounds of this invention orpharmaceutically acceptable salts thereof. In certain embodiments of themethods described herein, the method is carried out in vivo. In certainembodiments of the methods described herein, the method is carried outin vitro.

In certain embodiments of the methods, the compound is administered to asubject suffering from a T-cell mediated autoimmune disease. In someother embodiments, the subject is a transplant recipient suffering fromor predisposed to an allograft transplant rejection. In some otherembodiments, the compound is administered to a subject suffering from orpredisposed to develop a Type IV hypersensitivity reaction.

This invention also provides a method of inhibiting an activity of a JAKkinase, comprising contacting in vitro a JAK2 kinase with an amount of acompound effective to inhibit an activity of the JAK kinase wherein thecompound is selected from the compounds of this invention, orpharmaceutically acceptable salts thereof.

In a specific embodiment, the compounds of the invention, orpharmaceutically acceptable salts thereof, can be used to treat and/orprevent rejection in organ and/or tissue transplant recipients (i.e.,treat and/or prevent allograft rejection). Allografts can be rejectedthrough either a cell-mediated or humoral immune reaction of therecipient against transplant (histocompatibility) antigens present onthe membranes of the donor's cells. The strongest antigens are governedby a complex of genetic loci termed human leukocyte group A (HLA)antigens. Together with the ABO blood groups antigens, they are thechief transplantation antigens detectable in humans.

Rejection following transplantation can generally be broken into threecategories: hyperacute, occurring hours to days followingtransplantation; acute, occurring days to months followingtransplantation; and chronic, occurring months to years followingtransplantation.

Hyperacute rejection is caused mainly by the production of hostantibodies that attack the graft tissue. In a hyperacute rejectionreaction, antibodies are observed in the transplant vascular very soonafter transplantation. Shortly thereafter, vascular clotting occurs,leading to ischemia, eventual necrosis and death. The graft infarctionis unresponsive to known immunosuppressive therapies. Because HLAantigens can be identified in vitro, pre-transplant screening is used tosignificantly reduce hyperacute rejection. As a consequence of thisscreening, hyperacute rejection is relative uncommon today.

Acute rejection is thought to be mediated by the accumulation of antigenspecific cells in the graft tissue. The T-cell-mediated immune reactionagainst these antigens (i.e., HVGR or GVHR) is the principle mechanismof acute rejection. Accumulation of these cells leads to damage of thegraft tissue. It is believed that both CD4+ helper T-cells and CD8+cytotoxic T-cells are involved in the process, and that the antigen ispresented by donor and host dendritic cells. The CD4+ helper T-cellshelp recruit other effector cells, such as macrophages and eosinophils,to the graft. Accessing T-cell activation signal transduction cascades(for example, CD28, CD40L and CD2 cascades) are also involved.

The cell-mediated acute rejection can be reversed in many cases byintensifying immunotherapy. After successful reversal, severely damagedelements of the graft heal by fibrosis and the remainder of the graftappears normal. After resolution of acute rejection, dosages ofimmunosuppressive drugs can be reduced to very low levels.

Chronic rejection, which is a particular problem in renal transplants,often progresses insidiously despite increased immunosuppressivetherapy. It is thought to be due, in large part, to cell-mediated TypeIV hypersensitivity. The pathologic profile differs from that of acuterejection. The arterial endothelium is primarily involved, withextensive proliferation that may gradually occlude the vessel lumen,leading to ischemia, fibrosis, a thickened intima and atheroscleroticchanges. Chronic rejection is mainly due to a progressive obliterationof graft vasculature, and resembles a slow, vasculitic process.

In Type IV hypersensitivity, CD8 cytotoxic T-cells and CD4 helper Tcells recognize either intracellular or extracellular-synthesizedantigen when it is complexed, respectively, with either Class I or ClassII MHC molecules. Macrophages function as antigen-presenting cells andrelease IL-1, which promotes proliferation of helper T-cells. HelperT-cells release interferon gamma and IL-2, which together regulatedelayed hyperactivity reactions mediated by macrophage activation andimmunity mediated by T cells. In the case of organ transplant, thecytotoxic T-cells destroy the graft cells on contact.

Since JAK kinases play a critical role in the activation of T-cells, thepyrimidine-2-amine compounds or pharmaceutically acceptable saltsthereof described herein can be used to treat and/or prevent manyaspects of transplant rejection, and are particularly useful in thetreatment and/or prevention of rejection reactions that are mediated, atleast in part, by T-cells, such as HVGR or GVHR. The pyrimidine-2-aminecompounds can also be used to treat and/or prevent chronic rejection intransplant recipients, and in particular in renal transplant recipients.

This invention also provides a method of treating a T-cell mediatedautoimmune disease, comprising administering to a patient suffering fromsuch an autoimmune disease an amount of a compound effective to treatthe autoimmune disease wherein the compound is selected from thecompounds of the invention or pharmaceutically acceptable salts thereof.In certain embodiments of the methods the autoimmune disease is multiplesclerosis (MS), psoriasis, or Sjogren's syndrome.

Therapy using the pyrimidine-2-amine compounds, or pharmaceuticallyacceptable salts thereof, described herein can be applied alone, or theycan be applied in combination with or adjunctive to other commonimmunosuppressive therapies, such as, for example, mercaptopurine,corticosteroids such as prednisone, methylprednisolone and prednisolone,alkylating agents such as cyclophosphamide, calcineurin inhibitors suchas cyclosporine, sirolimus and tacrolimus, inhibitors of inosinemonophosphate dehydrogenase (IMPDH) such as mycophenolate, mycophenolatemofetil and azathioprine, and agents designed to suppress cellularimmunity while leaving the recipient's humoral immunologic responseintact, including various antibodies (for example, antilymphocyteglobulin (ALG), antithymocyte globulin (ATG), monoclonal anti-T-cellantibodies (OKT3)) and irradiation. These various agents can be used inaccordance with their standard or common dosages, as specified in theprescribing information accompanying commercially available forms of thedrugs (see also, the prescribing information in the 2006 Edition of ThePhysician's Desk Reference), the disclosures of which are incorporatedherein by reference. Azathioprine is currently available from SalixPharmaceuticals, Inc. under the brand name AZASAN; mercaptopurine iscurrently available from Gate Pharmaceuticals, Inc. under the brand namePURINETHOL; prednisone and prednisolone are currently available fromRoxane Laboratories, Inc.; Methyl prednisolone is currently availablefrom Pfizer; sirolimus (rapamycin) is currently available fromWyeth-Ayerst under the brand name RAPAMUNE; tacrolimus is currentlyavailable from Fujisawa under the brand name PROGRAF; cyclosporine iscurrent available from Novartis under the brand dame SANDIMMUNE andAbbott under the brand name GENGRAF; IMPDH inhibitors such asmycophenolate mofetil and mycophenolic acid are currently available fromRoche under the brand name CELLCEPT and Novartis under the brand nameMYFORTIC; azathioprine is currently available from Glaxo Smith Klineunder the brand name IMURAN; and antibodies are currently available fromOrtho Biotech under the brand name ORTHOCLONE, Novartis under the brandname SIMULECT (basiliximab) and Roche under the brand name ZENAPAX(daclizumab).

In addition, the pyrimidine-2-amine compounds of the invention could beadministered either in combination or adjunctively with an inhibitor ofa Syk kinase. Syk kinase is a tyrosine kinase known to play a criticalrole in Fcγ receptor signaling, as well as in other signaling cascades,such as those involving B-Cell receptor signaling (Tumer et al., (2000),Immunology Today 21:148-154) and integrins beta (1), beta (2) and beta(3) in neutrophils (Mocsavi et al., (2002), Immunity 16:547-558). Forexample, Syk kinase plays a pivotal role in high affinity IgE receptorsignaling in mast cells that leads to activation and subsequent releaseof multiple chemical mediators that trigger allergic attacks. However,unlike the JAK kinases, which help regulate the pathways involved indelayed, or cell-mediated Type IV hypersensitivity reactions, Syk kinasehelps regulate the pathways involved in immediate IgE-mediated, Type Ihypersensitivity reactions. Certain compounds that affect the Sykpathway may or may not also affect the JAK pathways.

Suitable Syk inhibitory compounds are described, for example, in U.S.patent application Ser. No. 10/355,543, filed Jan. 31, 2003 (publicationno. 2004/0029902); PCT Published Patent Application No. WO 03/063794;U.S. patent application Ser. No. 10/631,029, filed Jul. 29, 2003; PCTPublished Patent Application No. WO 2004/014382; U.S. patent applicationSer. No. 10/903,263, filed Jul. 30, 2004; PCT Published PatentApplication No. WO 2005/016893; U.S. patent application Ser. No.10/903,870, filed Jul. 30, 2004; PCT Patent Application No.PCT/US2004/24920, filed Jul. 30, 2004; U.S. Patent Application Ser. No.60/630,808, filed Nov. 24, 2004; U.S. Patent Application Ser. No.60/645,424, filed Jan. 19, 2005; and U.S. Patent Application Ser. No.60/654,620, filed Feb. 18, 2005, the disclosures of which areincorporated herein by reference in their entireties. Thepyrimidine-2-amine described herein and Syk inhibitory compounds couldbe used alone, or in combination with one or more conventionaltransplant rejection treatments, as described above.

In addition, the pyrimidine-2-amine compounds of the invention, orpharmaceutically acceptable salts thereof, can be used to treat orprevent these diseases or conditions in patients that are eitherinitially non-responsive (resistant) to, or that become non-responsiveto treatment with a Syk inhibitory compound, or one of the other currenttreatments for the particular disease. The pyrimidine-2-amine compoundsof the invention, or pharmaceutically acceptable salts thereof, couldalso be used in combination with Syk inhibitory compounds in patientsthat are Syk-compound resistant or non-responsive. SuitableSyk-inhibitory compounds with which the pyrimidine-2-amine compounds ofthe invention, or pharmaceutically acceptable salts thereof, can beadministered are provided supra.

This invention also provides a method of treating a T-cell mediatedautoimmune disease, comprising administering to a patient suffering fromsuch an autoimmune disease an amount of a compound effective to treatthe autoimmune disease wherein the compound is selected from thecompounds of the invention, as described herein, or pharmaceuticallyacceptable salts thereof, and the compound or pharmaceuticallyacceptable salt thereof is administered in combination with, oradjunctively to, a compound that inhibits Syk kinase with an IC₅₀ in therange of at least 10 μM.

This invention also provides a method of treating or preventingallograft transplant rejection in a transplant recipient, comprisingadministering to the transplant recipient an amount of a compoundeffective to treat or prevent the rejection wherein the compound isselected from the compounds of the invention, or pharmaceuticallyacceptable salts thereof, as described herein. In a further embodiment,the compound or pharmaceutically acceptable salt, is administered to atissue or an organ prior to transplanting the tissue or organ in thetransplant recipient.

This invention also provides a method of treating or preventingallograft transplant rejection in a transplant recipient, in which therejection is acute rejection, comprising administering to the transplantrecipient an amount of a compound effective to treat or prevent therejection wherein the compound is selected from the compounds of theinvention, or pharmaceutically acceptable salts thereof.

This invention also provides a method of treating or preventingallograft transplant rejection in a transplant recipient, in which therejection is chronic rejection, comprising administering to thetransplant recipient an amount of a compound effective to treat orprevent the rejection wherein the compound is selected from thecompounds of the invention, or pharmaceutically acceptable saltsthereof, as described herein.

This invention also provides a method of treating or preventingallograft transplant rejection in a transplant recipient, in which therejection is mediated by HVGR or GVHR, comprising administering to thetransplant recipient an amount of a compound effective to treat orprevent the rejection wherein the compound is selected from thecompounds of this invention, or pharmaceutically acceptable saltsthereof, as described herein.

This invention also provides a method of treating or preventingallograft transplant rejection in a transplant recipient, in which theallograft transplant is selected from a kidney, a heart, a liver and alung, comprising administering to the transplant recipient an amount ofa compound effective to treat or prevent the rejection wherein thecompound is selected from the compounds of this invention, orpharmaceutically acceptable salts thereof, as described herein.

This invention also provides a method of treating or preventingallograft transplant rejection in a transplant recipient, in which theallograft transplant is selected from a kidney, a heart, a liver and alung, comprising administering to the transplant recipient an amount ofa compound effective to treat or prevent the rejection wherein thecompound is selected from the compounds of the invention, orpharmaceutically acceptable salts thereof, as described herein, in whichthe compound or pharmaceutically acceptable salt is administered incombination with, or adjunctively to, another immunosuppressant.

This invention also provides a method of treating or preventingallograft transplant rejection in a transplant recipient, in which theallograft transplant is selected from a kidney, a heart, a liver and alung, comprising administering to the transplant recipient an amount ofa compound effective to treat or prevent the rejection wherein thecompound is selected from the compounds of the invention, orpharmaceutically acceptable salts thereof, as described herein, in whichthe compound or pharmaceutically acceptable salts is administered incombination with, or adjunctively to, another immunosuppressant, inwhich the immunosuppressant is selected from cyclosporine, tacrolimus,sirolimus, an inhibitor of IMPDH, mycophenolate, mycophanolate mofetil,an anti-T-Cell antibody and OKT3.

The pyrimidine-2-amine compounds of the invention, or pharmaceuticallyacceptable salts thereof, described herein are cytokine moderators ofIL-4 signaling. As a consequence, the pyrimidine-2-amine compounds ofthe invention, or pharmaceutically acceptable salts thereof, could slowthe response of Type I hypersensitivity reactions. Thus, in a specificembodiment, the pyrimidine-2-amine compounds of the invention, orpharmaceutically acceptable salts thereof, could be used to treat suchreactions, and therefore the diseases associated with, mediated by orcaused by such hypersensitivity reactions (for example, allergies),prophylactically. For example, an allergy sufferer could take one ormore of the JAK selective compounds described herein prior to expectedexposure to allergens to delay the onset or progress, or eliminatealtogether, an allergic response.

When used to treat or prevent such diseases, the pyrimidine-2-aminecompounds of the invention, or pharmaceutically acceptable saltsthereof, can be administered singly, as mixtures of one or morepyrimidine-2-amine compounds, or pharmaceutically acceptable saltsthereof, or in mixture or combination with other agents useful fortreating such diseases and/or the symptoms associated with suchdiseases. The pyrimidine-2-amine compounds, or pharmaceuticallyacceptable salts thereof, may also be administered in mixture or incombination with agents useful to treat other disorders or maladies,such as steroids, membrane stabilizers, 5-lipoxygenase (5LO) inhibitors,leukotriene synthesis and receptor inhibitors, inhibitors of IgE isotypeswitching or IgE synthesis, IgG isotype switching or IgG synthesis,β-agonists, tryptase inhibitors, aspirin, cyclooxygenase (COX)inhibitors, methotrexate, anti-TNF drugs, retuxin, PD4 inhibitors, p38inhibitors, PDE4 inhibitors, and antihistamines, to name a few. Thepyrimidine-2-amine compounds, or pharmaceutically acceptable saltsthereof, can be administered per se, or in the form of prodrugs or aspharmaceutical compositions comprising an active compound.

This invention also provides a method of treating or preventing a TypeIV hypersensitivity reaction, comprising administering to a subject anamount of a compound of effective to treat or prevent thehypersensitivity reaction wherein the compound is selected from thecompounds of this invention, or pharmaceutically acceptable saltsthereof, as described herein.

This invention also provides a method of treating or preventing a TypeIV hypersensitivity reaction, which is practical prophylactically,comprising administering to a subject an amount of a compound ofeffective to treat or prevent the hypersensitivity reaction wherein thecompound is selected from the compounds of this invention, orpharmaceutically acceptable salts thereof, as described herein, and isadministered prior to exposure to an allergen.

This invention also provides a method of inhibiting a signaltransduction cascade in which JAK2 kinase plays a role, comprisingcontacting a cell expressing a receptor involved in such a signalingcascade with a compound wherein the compound is selected from thecompounds of this invention, or pharmaceutically acceptable saltsthereof, as described herein.

In another embodiment, this invention provides a method of treating orpreventing a JAK kinase-mediated disease, comprising administering to asubject an amount of compound effective to treat or prevent the JAKkinase-mediated disease wherein the compound is selected from thecompounds of this invention, or pharmaceutically acceptable saltsthereof, as described herein.

This invention also provides a method of treating or preventing a JAKkinase-mediated disease, in which the JAK-mediated disease is HVGR orGVHR, comprising administering to a subject an amount of compoundeffective to treat or prevent the JAK kinase-mediated disease whereinthe compound is selected from the compounds of the invention, orpharmaceutically acceptable salts thereof, as described herein.

This invention also provides a method of treating or preventing a JAKkinase-mediated disease, in which the JAK-mediated disease is acuteallograft rejection, comprising administering to a subject an amount ofcompound effective to treat or prevent the JAK kinase-mediated diseasewherein the compound is selected from the compounds of the invention, orpharmaceutically acceptable salts thereof, as described herein.

This invention also provides a method of treating or preventing a JAKkinase-mediated disease, in which the JAK-mediated disease is chronicallograft rejection, comprising administering to a subject an amount ofcompound effective to treat or prevent the JAK kinase-mediated diseasewherein the compound is selected from the compounds of the invention, orpharmaceutically acceptable salts thereof, as described herein.

Active compounds of the invention, or pharmaceutically acceptable saltsthereof, typically inhibit the JAK/Stat pathway. The activity of aspecified compound as an inhibitor of a JAK kinase can be assessed invitro or in vivo. In some embodiments, the activity of a specifiedcompound can be tested in a cellular assay. Suitable assays includeassays that determine inhibition of either the phosphorylation activityor ATPase activity of a JAK kinase. Thus, a compound is said to inhibitan activity of a JAK kinase if it inhibits the phosphorylation or ATPaseactivity of a JAK kinase with an IC₅₀ of about 20 μM or less.

One means of assaying for such inhibition is detection of the effect ofthe pyrimidine-2-amine compounds on the upregulation of downstream geneproducts. In the Ramos/IL4 assay, B-cells are stimulated with thecytokine Interleukin-4 (IL-4) leading to the activation of the JAK/Statpathway through phosphorylation of the JAK family kinases, JAK1 andJAK3, which in turn phosphorylate and activate the transcription factorStat-6. One of the genes upregulated by activated Stat-6 is the lowaffinity IgE receptor, CD23. To study the effect of inhibitors (e.g.,the pyrimidine-2-amine compounds described herein) on the JAK1 and JAK3kinases, human Ramos B cells are stimulated with human IL-4. Twenty to24 hours post stimulation, cells are stained for upregulation of CD23and analyzed using flow cytometry (FACS). A reduction of the amount ofCD23 present compared to control conditions indicates the test compoundactively inhibits the JAK kinase pathway. An exemplary assay of thistype is described in greater detail in the Biological Examples describedbelow.

The biological activity of the compounds of the invention may further becharacterized by assaying the effect of the pyrimidine-2-amine compoundsdescribed herein on the proliferative response of primary human T-cells.In this assay, primary human T-cells derived from peripheral blood andpre-activated through stimulation of the T-cell receptor and CD28,proliferate in culture in response to the cytokine Interleukin-2 (IL-2).This proliferative response is dependent on the activation of JAK1 andJAK3 tyrosine kinases, which phosphorylate and activate thetranscription factor Stat-5. The primary human T-cells are incubatedwith the pyrimidine-2-amine compounds in the presence of IL-2 for 72hours and at the assay endpoint intracellular ATP concentrations aremeasured to assess cell viability. A reduction in cell proliferationcompared to control conditions is indicative of inhibition of the JAKkinase pathway. An exemplary assay of this type is described in greaterdetail in the Biological Examples described below.

The biological activity of the compounds of the invention mayadditionally be characterized by assaying the effect of thepyrimidine-2-amine compounds described herein on A549 lung epithelialcells and U937 cells. A549 lung epithelial cells and U937 cellsup-regulate ICAM-1 (CD54) surface expression in response to a variety ofdifferent stimuli. Therefore, using ICAM-1 expression as readout, testcompound effects on different signaling pathways can be assessed in thesame cell type. Stimulation with IL-1β through the IL-1β receptoractivates the TRAF6/NFκB pathway resulting in up-regulation of ICAM-1.IFNγ induces ICAM-1 up-regulation through activation of the JAK1/JAK2pathway. The up-regulation of ICAM-1 can be quantified by flow cytometryacross a compound dose curve and EC₅₀ values are calculated. Anexemplary assay of this type is described in greater detail in theBiological Examples described below.

Biologically active compounds of the invention, or pharmaceuticallyacceptable salts thereof, generally inhibit the JAK kinase pathway withan IC₅₀ in the range of about 1 mM or less, as measured in the assaysdescribed herein. Of course, skilled artisans will appreciate thatcompounds which exhibit lower IC₅₀s, for example on the order of 100 μM,75 μM, 50 μM, 40 μM, 30 μM, 20 μM, 15 μM, 10 μM, 5 μM, 1 μM, 500 nM, 100nM, 10 nM, 1 nM, or even lower, can be particularly useful intherapeutic applications. In instances where activity specific to aparticular cell type is desired, the compound can be assayed foractivity with the desired cell type and counter-screened for a lack ofactivity against other cell types. The desired degree of “inactivity” insuch counter screens, or the desired ratio of activity vs. inactivitymay vary for different situations, and can be selected by the user.

The pyrimidine-2-amine active compounds of the invention, orpharmaceutically acceptable salts thereof, also typically inhibit IL-4stimulated expression of CD23 in B-cells with an IC₅₀ in the range ofabout 20 μM or less, typically in the range of about 10 μM, 1 μM, 500nM, 100 nM, 10 nM, 1 nM, or even lower. A suitable assay that can beused is the assay described in the Biological Example 1 described below,entitled “Assay for Ramos B-Cell Line Stimulated with IL-4.” In certainembodiments, the active pyrimidine-2-amine compounds of the inventionhave an IC₅₀ of less than or equal to 5 μM, greater than 5 μM but lessthan 20 μM, greater than 20 μM, or greater than 20 μM but less than 50μM in the assay described in Biological Example 1.

Additionally, the pyrimidine-2-amine active compounds of the invention,or pharmaceutically acceptable salts thereof, also typically inhibit anactivity of an human primary T-cells with an IC₅₀ in the range of about20 μM or less, typically in the range of about 10 μM, 1 μM, 500 nM, 100nM, 10 nM, 1 nM, or even lower. The IC₅₀ against human primary T-cellscan be determined in a standard in vitro assay with isolated humanprimary T-cells. A suitable assay that can be used is the assaydescribed in the Biological Example 2 below, entitled “Primary HumanT-cell Proliferation Assay Stimulated with IL-2.” In certainembodiments, the active pyrimidine-2-amine compounds have an IC₅₀ ofless than or equal to 5 μM, greater than 5 μM but less than 20 μM,greater than 20 μM, or greater than 20 μM but less than 50 μM in theassay described in Biological Example 2.

The pyrimidine-2-amine active compounds of the invention, orpharmaceutically acceptable salts thereof, also typically inhibitexpression of ICAM1 (CD54) induced by IFNγ exposure in U937 or A549cells with an IC₅₀ in the range of about 20 μM or less, typically in therange of about 10 μM, 1 μM, 500 nM, 100 nM, 10 nM, 1 nM, or even lower.The IC₅₀ against expression of ICAM (CD54) in IFNγ stimulated cells canbe determined in a functional cellular assay with an isolated A549 orU937 cell line. Suitable assays that can be used are the assaysdescribed in Biological Examples 5 and 6 below, entitled “A549Epithelial Line Stimulated with IFNγ,” and “U937 IFNγ ICAM1 FACS Assay,”respectively. In certain embodiments, the active pyrimidine-2-aminecompounds have an IC₅₀ of less than or equal to 20 μM, greater than 20μM, or greater than 20 μM but less than 50 μM in the assays described inBiological Example 5 or Biological Example 6.

For purposes of this invention, the phrase “cell proliferative disorder”refers to a disorder characterized by abnormal proliferation of cells. Acell proliferative disorder does not imply any limitation with respectto the rate of cell growth, but merely indicates loss of normal controlsthat affect growth and cell division. Thus, in some embodiments, cellsof a cell proliferative disorder can have the same cell division ratesas normal cells but do not respond to signals that limit such growth.Within the ambit of “cell proliferative disorder” is neoplasm or tumor,which is an abnormal growth of tissue. Cancer refers to any of variousmalignant neoplasms characterized by the proliferation of cells thathave the capability to invade surrounding tissue and/or metastasize tonew colonization sites.

Accordingly, cell proliferative disorders treatable with the compoundsof the invention, or pharmaceutically acceptable salts thereof, relateto any disorder characterized by aberrant cell proliferation. Theseinclude various tumors and cancers, benign or malignant, metastatic ornon-metastatic. Cell proliferative disorders include a variety ofcancers, including, among others, cancer of the tongue, mouth, pharynx,esophagus, stomach, small intestine, colon, rectum, anus, liver,gallbladder, pancreas, larynx, lung and bronchus, bones and jointsincluding synovial sarcoma and osteosarcoma, melanomas including basalcell carcinoma, squamous carcinoma, breast, cervix, endometrium, ovary,vulva, vagina, prostate, testis, penis, urinary bladder, kidney andrenal pelvis, ureter, eye, brain including glioma, glioblastoma,astrocytoma, neuroblastoma, medulloblastoma, and thyroid. For example,cell proliferative disorders treatable with the compounds of theinvention, or pharmaceutically acceptable salts thereof, include, butare not limited to, the following:

a) proliferative disorders of the breast, which include, but are notlimited to, invasive ductal carcinoma, invasive lobular carcinoma,ductal carcinoma, lobular carcinoma in situ and metastatic breastcancer;

b) proliferative disorders of the skin, which include, but are notlimited to, basal cell carcinoma, squamous cell carcinoma, malignantmelanoma and Karposi's sarcoma;

c) proliferative disorders of the respiratory tract, which include, butare not limited to, small cell and non-small cell lung carcinoma,bronchial adema, pleuropulmonary blastoma and malignant mesothelioma;

d) proliferative disorders of the brain, which include, but are notlimited to, brain stem and hyptothalamic glioma, cerebellar and cerebralastrocytoma, medullablastoma, ependymal tumors, oligodendroglial,meningiomas and neuroectodermal and pineal tumors;

e) proliferative disorders of the male reproductive organs, whichinclude, but are not limited to, prostate cancer, testicular cancer andpenile cancer;

f) proliferative disorders of the female reproductive organs, whichinclude, but are not limited to, uterine cancer (endometrial), cervical,ovarian, vaginal, vulval cancers, uterine sarcoma and ovarian germ celltumor;

g) proliferative disorders of the digestive tract, which include, butare not limited to, anal, colon, colorectal, esophageal, gallbladder,stomach (gastric), pancreatic cancer, pancreatic cancer-Islet cell,rectal, small-intestine and salivary gland cancers;

h) proliferative disorders of the liver, which include, but are notlimited to, hepatocellular carcinoma, cholangiocarcinoma, mixedhepatocellular cholangiocarcinoma, primary liver cancer and metastaticliver cancer;

i) proliferative disorders of the eye, which include, but are notlimited to, intraocular melanoma, retinoblastoma, and rhabdomyosarcoma;

j) proliferative disorders of the head and neck, which include, but arenot limited to, laryngeal, hypopharyngeal, nasopharyngeal, oropharyngealcancers, and lip and oral cancer, squamous neck cancer, metastaticparanasal sinus cancer;

k) proliferative disorders of lymphocytic cells, which include, but arenot limited to, various T cell and B cell lymphomas, non-Hodgkinslymphoma, cutaneous T cell lymphoma, Hodgkins disease, and lymphoma ofthe central nervous system;

l) leukemias, which include, but are not limited to, acute myeloidleukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia,chronic myelogenous leukemia, and hairy cell leukemia,

m) proliferative disorders of the thyroid, which include, but are notlimited to, thyroid cancer, thymoma, malignant thymoma, medullarythyroid carcinomas, papillary thyroid carcinomas, multiple endocrineneoplasia type 2A (MEN2A), pheochromocytoma, parathyroid adenomas,multiple endocrine neoplasia type 2B (MEN2B), familial medullary thyroidcarcinoma (FMTC) and carcinoids;

n) proliferative disorders of the urinary tract, which include, but arenot limited to, bladder cancer;

o) sarcomas, which include, but are not limited to, sarcoma of the softtissue, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, andrhabdomyosarcoma;

p) proliferative disorders of the kidneys, which include, but are notlimited to, renal cell carcinoma, clear cell carcinoma of the kidney;and renal cell adenocarcinoma;

q) precursor B-lymphoblastic leukemia/lymphoma (precursor B-cell acutelymphoblastic leukemia), B-cell chronic lymphocytic leukemia/smalllymphocytic lymphoma, B-cell prolymphocytic leukemia, lymphoplasmacyticlymphoma, splenic marginal zone B-cell lymphoma, hairy cell leukemia,plasma cell myeloma/plasmacytoma, extranodal marginal zone B-celllymphoma of MALT type, nodal marginal zone B-cell lymphoma, follicularlymphoma, mantle-cell lymphoma, diffuse large B-cell lymphoma,mediastinal large B-cell lymphoma, primary effusion lymphoma andBurkitt's lymphoma/Burkitt cell leukemia

(r) precursor T-lymphoblastic lymphoma/leukemia (precursor T-cell acutelymphoblastic leukemia), T-cell prolymphocytic leukemia, T-cell granularlymphocytic leukemia, aggressive NK-cell leukemia, adult T-celllymphoma/leukemia (HTLV-1), extranodal NK/T-cell lymphoma, nasal type,enteropathy-type T-cell lymphoma, hepatosplenic gamma-delta T-celllymphoma, subcutaneous panniculitis-like T-cell lymphoma, mycosisfungoides/Sezary syndrome, anaplastic large-cell lymphoma, T/null cell,primary cutaneous type, peripheral T-cell lymphoma, not otherwisecharacterized, angioimmunoblastic T-cell lymphoma, anaplastic large-celllymphoma, T/null cell, and primary systemic type;

(s) nodular lymphocyte-predominant Hodgkin's lymphoma, nodular sclerosisHodgkin's lymphoma (grades 1 and 2), lymphocyte-rich classical Hodgkin'slymphoma, mixed cellularity Hodgkin's lymphoma, and lymphocyte depletionHodgkin's lymphoma;

(t) myelogenous leukemia (e.g., Philadelphia chromosome positive(t(9;22)(qq34;q11)), multiple myeloma, chronic neutrophilic leukemia,chronic eosinophilic leukemia/hypereosinophilic syndrome, chronicidiopathic myelofibrosis, polycythemia vera, essential thrombocythemia,chronic myelomonocytic leukemia, atypical chronic myelogenous leukemia,juvenile myelomonocytic leukemia, refractory anemia with ringedsideroblasts and without ringed sideroblasts, refractory cytopenia(myelodysplastic syndrome) with multilineage dysplasia, refractoryanemia (myelodysplastic syndrome) with excess blasts, 5q-syndrome, andmyelodysplastic syndrome with t(9;12)(q22;p12);

(u) AML with t(8;21)(q22;q22), AML1(CBF-alpha)/ETO, acute promyelocyticleukemia (AML with t(15;17)(q22;q11-12) and variants, PML/RAR-alpha),AML with abnormal bone marrow eosinophils (inv(16)(p13q22) ort(16;16)(p13;q11), CBFb/MYH11X), and AML with 11q23 (MLL) abnormalities,AML minimally differentiated, AML without maturation, AML withmaturation, acute myelomonocytic leukemia, acute monocytic leukemia,acute erythroid leukemia, acute megakaryocytic leukemia, acutebasophilic leukemia, and acute panmyelosis with myelofibrosis.

The antiproliferative effect of a combination therapy of the inventionmay be assessed by administering the compound of the invention to acultured tumor cell line. In the context of an in vitro assay,administration of a compound of the invention may be simply achieved bycontacting the cells in culture with the compound in amounts effectiveto inhibit cell proliferation. Alternatively, the antiproliferativeeffect of a compound of the invention may be assessed by administeringthe compound to an animal in an approved in vivo model for cellproliferation.

Examples of tumor cell lines derived from human tumors and available foruse in the in vivo studies include, but are not limited to, leukemiacell lines (e.g., CCRF-CEM, HL-60(TB), K-562, MOLT-4, RPM1-8226, SR,P388 and P388/ADR); non-small cell lung cancer cell lines (e.g.,A549/ATCC, EKVX, HOP-62, HOP-92, NCI-H226, NCI-H23, NCI-H322M, NCI-H460,NCI-H522 and LXFL 529); small cell lung cancer cell lines (e.g., DMS 114and SHP-77); colon cancer cell lines (e.g., COLO 205, HCC-2998, HCT-116,HCT-15, HT29, KM12, SW-620, DLD-1 and KM20L2); central nervous system(CNS) cancer cell lines (e.g., SF-268, SF-295, SF-539, SNB-19, SNB-75,U251, SNB-78 and XF 498); melanoma cell lines (e.g., LOX I MVI,MALME-3M, M14, SK-MEL-2, SK-MEL-28, SK-MEL-5, UACC-257, UACC-62,RPMI-7951 and M19-MEL); ovarian cancer cell lines (e.g., IGROV1,OVCAR-3, OVCAR-4, OVCAR-5, OVCAR-8 and SK-OV-3); renal cancer cell lines(e.g., 786-0, A498, ACHN, CAKI-1, RXF 393, SN12C, TK-10, UO-31, RXF-631and SN12K1); prostate cancer cell lines (e.g., PC-3 and DU-145); breastcancer cell lines (e.g., MCF7, NCI/ADR-RES, MDA-MB-231/ATCC, HS 578T,MDA-MB-435, BT-549, T-47D and MDA-MB-468); and thyroid cancer cell lines(e.g., SK-N-SH).

In some embodiments of the invention, the cell proliferative disordertreated by the compounds of the invention, or pharmaceuticallyacceptable salts thereof, is a hematopoietic neoplasm, which is aberrantgrowth of cells of the hematopoietic system. Hematopoietic malignanciescan have its origins in pluripotent stem cells, multipotent progenitorcells, oligopotent committed progenitor cells, precursor cells, andterminally differentiated cells involved in hematopoiesis. Somehematological malignancies are believed to arise from hematopoietic stemcells, which have the ability for self renewal. For instance, cellscapable of developing specific subtypes of acute myeloid leukemia (AML)upon transplantation display the cell surface markers of hematopoieticstem cells, implicating hematopoietic stem cells as the source ofleukemic cells. Blast cells that do not have a cell markercharacteristic of hematopoietic stem cells appear to be incapable ofestablishing tumors upon transplantation (Blaire et al., 1997, Blood89:3104-3112). The stem cell origin of certain hematologicalmalignancies also finds support in the observation that specificchromosomal abnormalities associated with particular types of leukemiacan be found in normal cells of hematopoietic lineage as well asleukemic blast cells. For instance, the reciprocal translocationt(9q34;22q11) associated with approximately 95% of chronic myelogenousleukemia appears to be present in cells of the myeloid, erythroid, andlymphoid lineage, suggesting that the chromosomal aberration originatesin hematopoietic stem cells. A subgroup of cells in certain types of CMLdisplays the cell marker phenotype of hematopoietic stem cells.

Although hematopoietic neoplasms often originate from stem cells,committed progenitor cells or more terminally differentiated cells of adevelopmental lineage can also be the source of some leukemias. Forexample, forced expression of the fusion protein Bcr/Abl (associatedwith chronic myelogenous leukemia) in common myeloid progenitor orgranulocyte/macrophage progenitor cells produces a leukemic-likecondition. Moreover, some chromosomal aberrations associated withsubtypes of leukemia are not found in the cell population with a markerphenotype of hematopoietic stem cells, but are found in a cellpopulation displaying markers of a more differentiated state of thehematopoietic pathway (Turhan et al., 1995, Blood 85:2154-2161). Thus,while committed progenitor cells and other differentiated cells may haveonly a limited potential for cell division, leukemic cells may haveacquired the ability to grow unregulated, in some instances mimickingthe self-renewal characteristics of hematopoietic stem cells (Passegueet al., Proc. Natl. Acad. Sci. USA, 2003, 100:11842-9).

In some embodiments of the invention, the hematopoietic neoplasm treatedby the compounds of the invention, or pharmaceutically acceptable saltsthereof, is a lymphoid neoplasm, where the abnormal cells are derivedfrom and/or display the characteristic phenotype of cells of thelymphoid lineage. Lymphoid neoplasms can be subdivided into B-cellneoplasms, T and NK-cell neoplasms, and Hodgkin's lymphoma. B-cellneoplasms can be further subdivided into precursor B-cell neoplasm andmature/peripheral B-cell neoplasm. Exemplary B-cell neoplasms areprecursor B-lymphoblastic leukemia/lymphoma (precursor B-cell acutelymphoblastic leukemia) while exemplary mature/peripheral B-cellneoplasms are B-cell chronic lymphocytic leukemia/small lymphocyticlymphoma, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma,splenic marginal zone B-cell lymphoma, hairy cell leukemia, plasma cellmyeloma/plasmacytoma, extranodal marginal zone B-cell lymphoma of MALTtype, nodal marginal zone B-cell lymphoma, follicular lymphoma,mantle-cell lymphoma, diffuse large B-cell lymphoma, mediastinal largeB-cell lymphoma, primary effusion lymphoma, and Burkitt'slymphoma/Burkitt cell leukemia. T-cell and Nk-cell neoplasms are furthersubdivided into precursor T-cell neoplasm and mature (peripheral) T-cellneoplasms. Exemplary precursor T-cell neoplasm is precursorT-lymphoblastic lymphoma/leukemia (precursor T-cell acute lymphoblasticleukemia) while exemplary mature (peripheral) T-cell neoplasms areT-cell prolymphocytic leukemia T-cell granular lymphocytic leukemia,aggressive NK-cell leukemia, adult T-cell lymphoma/leukemia (HTLV-1),extranodal NK/T-cell lymphoma, nasal type, enteropathy-type T-celllymphoma, hepatosplenic gamma-delta T-cell lymphoma, subcutaneouspanniculitis-like T-cell lymphoma, Mycosis fungoides/Sezary syndrome,Anaplastic large-cell lymphoma, T/null cell, primary cutaneous type,Peripheral T-cell lymphoma, not otherwise characterized,Angioimmunoblastic T-cell lymphoma, Anaplastic large-cell lymphoma,T/null cell, primary systemic type. The third member of lymphoidneoplasms is Hodgkin's lymphoma, also referred to as Hodgkin's disease.Exemplary diagnosis of this class that can be treated with the compoundsof the invention, include, among others, nodular lymphocyte-predominantHodgkin's lymphoma, and various classical forms of Hodgkin's disease,exemplary members of which are Nodular sclerosis Hodgkin's lymphoma(grades 1 and 2), Lymphocyte-rich classical Hodgkin's lymphoma, Mixedcellularity Hodgkin's lymphoma, and Lymphocyte depletion Hodgkin'slymphoma. In various embodiments, any of the lymphoid neoplasms that areassociated with aberrant JAK activity can be treated with the JAKinhibitory compounds.

In some embodiments of the invention, the hematopoietic neoplasm treatedby the compounds of the invention, or pharmaceutically acceptable saltsthereof, is a myeloid neoplasm. This group comprises a large class ofcell proliferative disorders involving or displaying the characteristicphenotype of the cells of the myeloid lineage. Myeloid neoplasms can besubdivided into myeloproliferative diseases,myelodysplastic/myeloproliferative diseases, myelodysplastic syndromes,and acute myeloid leukemias. Exemplary myeloproliferative diseases arechronic myelogenous leukemia (e.g., Philadelphia chromosome positive(t(9;22)(qq34;q11)), chronic neutrophilic leukemia, chronic eosinophilicleukemia/hypereosinophilic syndrome, chronic idiopathic myelofibrosis,polycythemia vera, and essential thrombocythemia. Exemplarymyelodysplastic/myeloproliferative diseases are chronic myelomonocyticleukemia, atypical chronic myelogenous leukemia, and juvenilemyelomonocytic leukemia. Exemplary myelodysplastic syndromes arerefractory anemia, with ringed sideroblasts and without ringedsideroblasts, refractory cytopenia (myelodysplastic syndrome) withmultilineage dysplasia, refractory anemia (myelodysplastic syndrome)with excess blasts, 5q-syndrome, and myelodysplastic syndrome. Invarious embodiments, any of the myeloid neoplasms that are associatedwith aberrant JAK activity can be treated with the JAK inhibitorycompounds.

In some embodiments of the invention, the JAK inhibitory compounds ofthe invention, or pharmaceutically acceptable salts thereof, can be usedto treat acute myeloid leukemias (AML), which represent a large class ofmyeloid neoplasms having its own subdivision of disorders. Thesesubdivisions include, among others, AMLs with recurrent cytogenetictranslocations, AML with multilineage dysplasia, and other AML nototherwise categorized. Exemplary AMLs with recurrent cytogenetictranslocations include, among others, AML with t(8;21)(q22;q22),AML1(CBF-alpha)/ETO, Acute promyelocytic leukemia (AML witht(15;17)(q22;q11-12) and variants, PML/RAR-alpha), AML with abnormalbone marrow eosinophils (inv(16)(p13q22) or t(16;16)(p13;q11),CBFb/MYH11X), and AML with 11q23 (MLL) abnormalities. Exemplary AML withmultilineage dysplasia are those that are associated with or withoutprior myelodysplastic syndrome. Other acute myeloid leukemias notclassified within any definable group include, AML minimallydifferentiated, AML without maturation, AML with maturation, Acutemyelomonocytic leukemia, Acute monocytic leukemia, Acute erythroidleukemia, Acute megakaryocytic leukemia, Acute basophilic leukemia, andAcute panmyelosis with myelofibrosis.

Animal models useful for testing the efficacy of compounds to treat orprevent the various diseases or conditions described above arewell-known in the art. Suitable animal models of hypersensitivity orallergic reactions are described in Foster, (1995) Allergy 50(21Suppl):6-9, discussion 34-38 and Tumas et al., (2001), J. Allergy Clin.Immunol. 107(6):1025-1033. Suitable animal models of allergic rhinitisare described in Szelenyi et al., (2000), Arzneimittelforschung50(11):1037-42; Kawaguchi et al., (1994), Clin. Exp. Allergy24(3):238-244 and Sugimoto et al., (2000), Immunopharmacology 48(1):1-7.Suitable animal models of allergic conjunctivitis are described inCarreras et al., (1993), Br. J. Ophthalmol. 77(8):509-514; Saiga et al.,(1992), Ophthalmic Res. 24(1):45-50; and Kunert et al., (2001), Invest.Ophthalmol. Vis. Sci. 42(11):2483-2489. Suitable animal models ofsystemic mastocytosis are described in O'Keefe et al., (1987), J. Vet.Intern. Med. 1(2):75-80 and Bean-Knudsen et al., (1989), Vet. Pathol.26(1):90-92. Suitable animal models of hyper IgE syndrome are describedin Claman et al., (1990), Clin. Immunol. Immunopathol. 56(1):46-53.Suitable animal models of B-cell lymphoma are described in Hough et al.,(1998), Proc. Natl. Acad. Sci. USA 95:13853-13858 and Hakim et al.,(1996), J. Immunol. 157(12):5503-5511. Suitable animal models of atopicdisorders such as atopic dermatitis, atopic eczema and atopic asthma aredescribed in Chan et al., (2001), J. Invest. Dermatol. 117(4):977-983and Suto et al., (1999), Int. Arch. Allergy Immunol. 120(Suppl 1):70-75.Suitable animal models of transplant rejection, such as models of HVGRare described in O'Shea et al., (2004), Nature Reviews Drug Discovery3:555-564; Cetkovic-Curlje & Tibbles, (2004), Current PharmaceuticalDesign 10:1767-1784; and Chengelian et al., (2003), Science 302:875-878.Suitable animal models of polycythemia vera, essential thrombocythemiaand primary myelofibrosis are described in Shimoda, (2008) Leukemia22(1):87-95; Lacout, (2006) Blood 108(5):1652-60; and Wernig, (2006)Blood 107(11):4274-81.

Pharmaceutical Compositions of the Invention and Administration

Administration of the compounds of the invention, or theirpharmaceutically acceptable salts, in pure form or in an appropriatepharmaceutical composition, can be carried out via any of the acceptedmodes of administration of agents for serving similar utilities. Thepharmaceutical compositions of the invention can be prepared bycombining a compound of the invention with an appropriatepharmaceutically acceptable carrier, diluent or excipient, and may beformulated into preparations in solid, semi-solid, liquid or gaseousforms, such as tablets, capsules, powders, granules, ointments,solutions, suppositories, injections, inhalants, gels, microspheres, andaerosols. Typical routes of administering such pharmaceuticalcompositions include, without limitation, oral, topical, transdermal,inhalation, parenteral, sublingual, buccal, rectal, vaginal, andintranasal. The term parenteral, as used herein, includes subcutaneousinjections, intravenous, intramuscular, intrasternal injection orinfusion techniques. Pharmaceutical compositions of the invention areformulated so as to allow the active ingredients contained therein to bebioavailable upon administration of the composition to a patient.Compositions that will be administered to a subject or patient take theform of one or more dosage units where, for example, a tablet may be asingle dosage unit, and a container of a compound of the invention inaerosol form may hold a plurality of dosage units. Actual methods ofpreparing such dosage forms are known, or will be apparent, to thoseskilled in this art; for example, see Remington: The Science andPractice of Pharmacy, 20th Edition (Philadelphia College of Pharmacy andScience, 2000). The composition to be administered will, in any event,contain a therapeutically effective amount of a compound of theinvention, or a pharmaceutically acceptable salt thereof, for treatmentof a disease or condition of interest in accordance with the teachingsof this invention.

A pharmaceutical composition of the invention may be in the form of asolid or liquid. In one aspect, the carrier(s) are particulate, so thatthe compositions are, for example, in tablet or powder form. Thecarrier(s) may be liquid, with the compositions being, for example, anoral oil, injectable liquid or an aerosol, which is useful in, forexample, inhalatory administration.

When intended for oral administration, the pharmaceutical composition ispreferably in either solid or liquid form, where semi-solid,semi-liquid, suspension and gel forms are included within the formsconsidered herein as either solid or liquid.

As a solid composition for oral administration, the pharmaceuticalcomposition may be formulated into a powder, granule, compressed tablet,pill, capsule, chewing gum, wafer or the like form. Such a solidcomposition will typically contain one or more inert diluents or ediblecarriers. In addition, one or more of the following may be present:binders such as carboxymethylcellulose, ethyl cellulose,microcrystalline cellulose, gum tragacanth or gelatin; excipients suchas starch, lactose or dextrins, disintegrating agents such as alginicacid, sodium alginate, Primogel, corn starch and the like; lubricantssuch as magnesium stearate or Sterotex; glidants such as colloidalsilicon dioxide; sweetening agents such as sucrose or saccharin; aflavoring agent such as peppermint, methyl salicylate or orangeflavoring; and a coloring agent.

When the pharmaceutical composition is in the form of a capsule, forexample, a gelatin capsule, it may contain, in addition to materials ofthe above type, a liquid carrier such as polyethylene glycol or oil.

The pharmaceutical composition may be in the form of a liquid, forexample, an elixir, syrup, solution, emulsion or suspension. The liquidmay be for oral administration or for delivery by injection, as twoexamples. When intended for oral administration, preferred compositioncontain, in addition to the present compounds, one or more of asweetening agent, preservatives, dye/colorant and flavor enhancer. In acomposition intended to be administered by injection, one or more of asurfactant, preservative, wetting agent, dispersing agent, suspendingagent, buffer, stabilizer and isotonic agent may be included.

The liquid pharmaceutical compositions of the invention, whether they besolutions, suspensions or other like form, may include one or more ofthe following adjuvants: sterile diluents such as water for injection,saline solution, preferably physiological saline, Ringer's solution,isotonic sodium chloride, fixed oils such as synthetic mono ordiglycerides which may serve as the solvent or suspending medium,polyethylene glycols, glycerin, propylene glycol or other solvents;antibacterial agents such as benzyl alcohol or methyl paraben;antioxidants such as ascorbic acid or sodium bisulfite; chelating agentssuch as ethylenediaminetetraacetic acid; buffers such as acetates,citrates or phosphates and agents for the adjustment of tonicity such assodium chloride or dextrose. The parenteral preparation can be enclosedin ampoules, disposable syringes or multiple dose vials made of glass orplastic. Physiological saline is a preferred adjuvant. An injectablepharmaceutical composition is preferably sterile.

A liquid pharmaceutical composition of the invention intended for eitherparenteral or oral administration should contain an amount of a compoundof the invention such that a suitable dosage will be obtained.Typically, this amount is at least 0.01% of a compound of the inventionin the composition. When intended for oral administration, this amountmay be varied to be between 0.1 and about 70% of the weight of thecomposition. Preferred oral pharmaceutical compositions contain betweenabout 4% and about 75% of the compound of the invention. Preferredpharmaceutical compositions and preparations according to the presentinvention are prepared so that a parenteral dosage unit contains between0.01 to 10% by weight of the compound prior to dilution of theinvention.

The pharmaceutical composition of the invention may be intended fortopical administration, in which case the carrier may suitably comprisea solution, emulsion, ointment or gel base. The base, for example, maycomprise one or more of the following: petrolatum, lanolin, polyethyleneglycols, bee wax, mineral oil, diluents such as water and alcohol, andemulsifiers and stabilizers. Thickening agents may be present in apharmaceutical composition for topical administration. If intended fortransdermal administration, the composition may include a transdermalpatch or iontophoresis device. Topical formulations may contain aconcentration of the compound of the invention from about 0.1 to about10% w/v (weight per unit volume).

The pharmaceutical composition of the invention may be intended forrectal administration, in the form, for example, of a suppository, whichwill melt in the rectum and release the drug. The composition for rectaladministration may contain an oleaginous base as a suitablenonirritating excipient. Such bases include, without limitation,lanolin, cocoa butter and polyethylene glycol.

The pharmaceutical composition of the invention may include variousmaterials, which modify the physical form of a solid or liquid dosageunit. For example, the composition may include materials that form acoating shell around the active ingredients. The materials that form thecoating shell are typically inert, and may be selected from, forexample, sugar, shellac, and other enteric coating agents.Alternatively, the active ingredients may be encased in a gelatincapsule.

The pharmaceutical composition of the invention in solid or liquid formmay include an agent that binds to the compound of the invention andthereby assists in the delivery of the compound. Suitable agents thatmay act in this capacity include a monoclonal or polyclonal antibody, aprotein or a liposome.

The pharmaceutical composition of the invention may consist of dosageunits that can be administered as an aerosol. The term aerosol is usedto denote a variety of systems ranging from those of colloidal nature tosystems consisting of pressurized packages. Delivery may be by aliquefied or compressed gas or by a suitable pump system that dispensesthe active ingredients. Aerosols of compounds of the invention may bedelivered in single phase, bi-phasic, or tri-phasic systems in order todeliver the active ingredient(s). Delivery of the aerosol includes thenecessary container, activators, valves, subcontainers, and the like,which together may form a kit. One of ordinary skill in the art, withoutundue experimentation may determine preferred aerosols.

The pharmaceutical compositions of the invention may be prepared bymethodology well known in the pharmaceutical art. For example, apharmaceutical composition intended to be administered by injection canbe prepared by combining a compound of the invention with sterile,distilled water so as to form a solution. A surfactant may be added tofacilitate the formation of a homogeneous solution or suspension.Surfactants are compounds that non-covalently interact with the compoundof the invention so as to facilitate dissolution or homogeneoussuspension of the compound in the aqueous delivery system.

The compounds of the invention, or their pharmaceutically acceptablesalts, are administered in a therapeutically effective amount, whichwill vary depending upon a variety of factors including the activity ofthe specific compound employed; the metabolic stability and length ofaction of the compound; the age, body weight, general health, sex, anddiet of the patient; the mode and time of administration; the rate ofexcretion; the drug combination; the severity of the particular disorderor condition; and the subject undergoing therapy. Generally, atherapeutically effective daily dose is (for a 70 kg mammal) from about0.001 mg/kg (i.e., 0.70 mg) to about 100 mg/kg (i.e., 7.0 gm);preferably a therapeutically effective dose is (for a 70 kg mammal) fromabout 0.01 mg/kg (i.e., 0.7 mg) to about 50 mg/kg (i.e., 3.5 gm); morepreferably a therapeutically effective dose is (for a 70 kg mammal) fromabout 1 mg/kg (i.e., 70 mg) to about 25 mg/kg (i.e., 1.75 gm).

Compounds of the invention, or pharmaceutically acceptable saltsthereof, may also be administered simultaneously with, prior to, orafter administration of one or more other therapeutic agents. Suchcombination therapy includes administration of a single pharmaceuticaldosage formulation which contains a compound of the invention and one ormore additional active agents, as well as administration of the compoundof the invention and each active agent in its own separatepharmaceutical dosage formulation. For example, a compound of theinvention and the other active agent can be administered to the patienttogether in a single oral dosage composition such as a tablet orcapsule, or each agent administered in separate oral dosageformulations. Where separate dosage formulations are used, the compoundsof the invention and one or more additional active agents can beadministered at essentially the same time, i.e., concurrently, or atseparately staggered times, i.e., sequentially; combination therapy isunderstood to include all these regimens.

Preparation of the Compounds of the Invention

The following Reaction Schemes illustrate methods to make compounds offormula (I), as isolated stereoisomers or mixtures thereof, or aspharmaceutically acceptable salts thereof. In particular, the followingReaction Scheme illustrates a method to make certain compounds offormula (I), i.e., the compounds of formula (Ia):

where n, m, Y, R¹, R², R³, R⁴ and R⁵ are as described above in theEmbodiments section for compounds of formula (Ia), as isolatedstereoisomers or mixtures thereof, or as pharmaceutically acceptablesalts thereof. It is understood that in the following Reaction Schemes,combinations of substituents and/or variables of the depicted formulaeare permissible only if such contributions result in stable compounds.It is also understood that other compounds of formula (I), particularly,compounds of formulae (Ia-1), (Ia-1a), (Ia-1b), (Ia-1c), (Ia-1d),(Ia-1e), (Ia-1f), (Ia-1g), (Ia-1h), (Ia-1i), (Ia-1j), (Ia-1k), (Ia-1l),(Ia-2), (Ia-2a), (Ia-2b), (Ia-2c), (Ia-2d), (Ia-2e), (Ia-2f), (Ia-2g),(Ia-2h), (Ia-2i), (Ia-2j), (Ia-2k) and (Ia-2l), and other compounds ofthe formula (I) not specifically disclosed herein, may be prepared byone skilled in the organic chemistry field by the methods disclosedherein (by utilizing the appropriately substituted starting materialsand modifying the parameters of the synthesis as needed utilizingmethods known to one skilled in the art) or by known methods.

Skilled artisans will recognize that in some instances, startingmaterials and intermediates in the preparation of the compounds of theinvention may include functional groups that require protection duringsynthesis. The exact identity of any protecting group(s) used willdepend upon the identity of the functional group being protected, andwill be apparent to those of skill in the art. Guidance for selectingappropriate protecting groups, as well as synthetic strategies for theirattachment and removal, can be found, for example, in Greene & Wuts,Greene's Protective Groups in Organic Synthesis, 3d Edition, John Wiley& Sons, Inc., New York (1999) and the references cited therein(hereinafter “Greene & Wuts”).

Thus, protecting group refers to a group of atoms that, when attached toa reactive functional group in a molecule, mask, reduce or prevent thereactivity of the functional group. Typically, a protecting group can beselectively removed as desired during the course of a synthesis.Examples of protecting groups can be found in Greene and Wuts, asmentioned above, and additionally, in Harrison et al., Compendium ofSynthetic Organic Methods, Vols. 1-8, 1971-1996, John Wiley & Sons, NY.Representative amino protecting groups include, but are not limited to,formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl (“CBZ”),tert-butoxycarbonyl (“Boc”), trimethylsilyl (“TMS”),2-trimethylsilyl-ethanesulfonyl (“TES”), trityl and substituted tritylgroups, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl (“FMOC”),nitro-veratryloxycarbonyl (“NVOC”) and the like. Representative hydroxylprotecting groups include, but are not limited to, those where thehydroxyl group is either acylated to form acetate and benzoate esters oralkylated to form benzyl and trityl ethers, as well as alkyl ethers,tetrahydropyranyl ethers, trialkylsilyl ethers (e.g., TMS or TIPPSgroups) and allyl ethers.

It will also be appreciated by those skilled in the art, although suchprotected derivatives of compounds of this invention may not possesspharmacological activity as such, they may be administered to a mammaland thereafter metabolized in the body to form compounds of theinvention which are pharmacologically active. Such derivatives maytherefore be described as “prodrugs”. All prodrugs of compounds of thisinvention are included within the scope of the invention.

In general, starting components may be obtained from sources such asSigma Aldrich, Lancaster Synthesis, Inc., Maybridge, Matrix Scientific,TCI, and Fluorochem USA, etc. or synthesized according to sources knownto those skilled in the art (see, for example, Advanced OrganicChemistry: Reactions, Mechanisms, and Structure, 5th edition (Wiley,December 2000)) or prepared as described herein. ¹H NMR spectra arerecorded in CDCl₃, DMSO-d₆, CD₃OD, or Acetone-d₆ with trimethylsilane(TMS) as internal reference using Gemini 300 MHz instrument. Reagentsand solvents were purchased from commercial sources and used withoutfurther purification. Flash column chromatography was conducted usingsilica gel (230-400 mesh) under a positive pressure of nitrogen. LCMSspectra for purity and mass were recorded using Waters LCMS instruments.Deionized water was used to dilute the reactions and wash the products.Brine used was prepared by dissolving sodium chloride into deionizedwater to saturation point.

A. Preparation of Compounds of Formula (Ia1)

Compounds of formula (Ia1) are compounds of formula (Ia), as describedabove in the Embodiments, where R⁴ in the compounds of formula (Ia) hasthe following formula:

Compounds of formula (Ia1) can be prepared as described below inReaction Scheme 1 wherein n, m, Y, R¹, R² and R³ are as described abovein the Embodiments for compounds of formula (Ia); q is 0, 1 or 2; Y¹ is═C(R⁶) (where R⁶ is as described above for R⁶ in the compounds offormula (I), as described above in the Summary of the Invention) or ═N—;each Z is chloro or bromo; R^(4a) is —N(R⁶)R⁷ (where R⁶ and R⁷ are eachas described above in the compounds of formula (I), as described abovein the Summary of the Invention); and each R^(4b), if present, isindependently selected from the group consisting of alkyl, halo andhaloalkyl. Preferably, for compounds of formula (Ia1), q is 0.

Compounds of formula (A), formula (B) and formula (D) are commerciallyavailable, or can be prepared according to methods known to one skilledin the art, or by the methods disclosed herein.

In general, compounds of formula (Ia1) can be prepared by methods knownto one skilled in the art and/or by the methods depicted above inReaction Scheme 1 wherein a compound of formula (B) is coupled with acompound of formula (A) under suitable aromatic coupling conditions,such as, but not limited to, Suzuki coupling conditions known to oneskilled in the art to provide a compound of formula (C). Compounds (C)are then treated with a compound of formula (D) under SNAr (SubstitutionNucleophilic Aromatic) conditions known to one skill in the art toprovide a compound of formula (Ia1).

A specific example of the preparation of a compound of the invention bythe method disclosed above in Reaction Scheme 1 is the preparation ofthe compound (1), which is a compound of formula (Ia1), as shown belowin Reaction Scheme 1A.

Details of the preparation of compound (1) are provided below in theappropriate Synthetic Preparation and/or Synthetic Example below.

Alternatively, compounds of formula (Ia1) (where n is 0) can beprepared, for example, using a convergent synthesis as described belowin Reaction Scheme 2. In particular, compounds of formula (Ia1-1), whichare compounds of formula (Ia1) where n is 0 and R^(4a) is—N(R^(6b))R^(7b) (where R^(6b) and R^(7b) are independently selectedfrom hydrogen or alkyl, or together with the common nitrogen to whichthey are attached, form an optionally substituted N-heterocyclyl), canbe prepared as described below in Reaction Scheme 2 wherein m, Y, R¹,and R² are as described above in the Embodiments for compounds offormula (Ia); q is 0, 1 or 2; Y¹ is ═C(R⁶) (where R⁶ is as describedabove for R⁶ in compounds of formula (Ia)) or ═N—; Z is chloro or bromo;each R^(4b), if present, is independently selected from the groupconsisting of alkyl, halo and haloalkyl. Preferably, for compounds offormula (Ia1), q is 0, and R^(6b) and R^(7b) are independently selectedfrom hydrogen or alkyl, or together with the common nitrogen to whichthey are attached, form an optionally substituted N-heterocyclyl.

Compounds of formula (D), formula (E), formula (F), formula (H) andformula (M) are commercially available, or can be prepared according tomethods known to one skilled in the art or by the methods disclosedherein.

In general, compounds of formula (Ia1-1) can be prepared by methodsknown to one of ordinary skill in the art and/or by the methods depictedabove in the Reaction Scheme 2 wherein, for example, α,β-unsaturatedenamines of formula (G) are formed from the corresponding ketones offormula (E), for example, via Wittig-type homologation using compound(F). Guanidines of formula (K) are prepared, for example, via conversionof anilines of formula (D) to the corresponding BOC-protected guanidinesof formula (J), followed by deprotection. Guanidines of formula (K) andα,β-unsaturated enamines of formula (G) are then reacted to form thepyrimidine-2-amines of formula (L), which can be further converted tothe pyrimidine-2-amines of formula (Ia1-1) via, for example, standardSNAr reaction conditions using, for example, an nucleophilic amine offormula (M).

A specific example of the preparation of a compound of the invention bythe method disclosed above in Reaction Scheme 2 is the preparation ofcompound (1), as shown below in Reaction Scheme 2A.

Details of the preparation of compound (I) by this method are providedbelow in the appropriate Synthetic Preparations and Synthetic Examples.

Another specific example of the preparation of a compound of theinvention by the method disclosed above in Reaction Scheme 2 is thepreparation of compound (10), as shown below in Reaction Scheme 2B.

In this example, nucleophilic amine (Mb) was added to pyridine (Ea)prior to formation of the enamine, pyrimidine, etc. Consistent with theprior example, ketone (Eb) is homologated to enamine (Gb). Enamine (Gb)is reacted with guanidine (Ka) to form pyrimidine-2-amine (10). Detailsof the preparation of compound (10) by this method are provided below inthe appropriate Synthetic Preparations and Synthetic Examples.

The pharmaceutically acceptable salts of the compounds of the inventioncan be formed by conventional means, such as by reacting the free baseform of the product with one or more equivalents of the appropriate acidin a solvent or medium in which the salt is insoluble, or in a solventsuch as water which is removed in vacuo or by freeze drying or byexchanging the anions of an existing salt for another anion on asuitable ion exchange resin.

The following specific Synthetic Preparations (for starting materialsand intermediates) and Synthetic Examples (for compounds of theinvention) are provided as a guide to assist in the practice of theinvention, and are not intended as a limitation on the scope of theinvention. The number following each compound below refers to its numberin Table 2 or Table 3, as discussed in more detail below.

Synthetic Preparation 1 Compounds of Formula (Ca)2-Chloro-4-(6-dimethylaminopyridin-3-yl)pyrimidine

A flask containing 2,4-dichloropyrimidine (0.5 g, 3.35 mmol),[6-(dimethylamino)pyridin-3-yl]boronic acid (0.61 g, 3.67 mmol) and DME(10 mL) was purged with N₂ for 10 min.Dichloro[1,1′-bis(diphenylphosphino)]ferrocene-palladium CH₂Cl₂ adduct(0.37 g, 0.50 mmol) and triethylamine (0.85 g, 1.17 mL, 8.33 mmol) wereadded successively to the flask with continuous bubbling of N₂ including5 min. post addition of the reagents. The reaction mixture was stirredand heated at 90° C. for 5 h. Reaction progress was monitored by TLC(silica gel). The reaction mixture was concentrated and diluted withwater, wherein a tan solid formed. The solid was filtered, dried andpurified by silica gel column chromatography using 50% EtOAc/hexanes aseluent to provide 2-chloro-4-(6-dimethylaminopyridin-3-yl)pyrimidine asa white solid (0.56 g, 71%); ¹H NMR (DMSO-d6): δ 8.91 (s, 1H), 8.60 (d,1H, J=5.3 Hz), 8.20 (dd, 1H, J=2.3 and 9.1 Hz), 7.95 (d, 1H, J=5.3 Hz),6.74 (d, 1H, J=9.1 Hz), 3.11 (s, 3H). LCMS: purity: 98%; MS (m/e): 235(MH⁺).

Synthetic Preparation 2 Compounds of Formula (Da)3-Methyl-4-[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]aniline

A. (1S,4S)-2-Methyl-2,5-diazabicyclo[2.2.1]heptane.2HBr (6 g, 21.89mmol) (which can be prepared by similar methods as described in Braish,T. F et al., J. Org. Chem. (1990), Vol. 55, pp. 1684-1687),2-fluoro-5-nitrotoluene (2.61 g, 16.82 mmol) and K₂CO₃ (10.57 g, 76.46mmol) in 30 mL NMP were heated at 110° C. for 14 h while stirring. Thereaction mixture was cooled to ambient temperature, poured ontoice-water and stirred until precipitate formation. The yellow solidformed was collected by filtration and washed with 15% EtOAc/hexanes toprovide2-[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]-5-nitrotoluene(3.4 g, 79%) in 98% purity; ¹H NMR (DMSO-d₆): δ 7.88-7.55 (m, 2H), 6.69(d, 1H, J=8.8 Hz), 4.37 (s, 1H), 3.64 (dd, 1H, J=2.0 and 9.9 Hz),3.38-3.55 (m, 2H), 2.81 (d, 1H, J=9.9 Hz), 2.65 (d, 1H, J=9.9 Hz), 2.33(s, 3H), 2.23 (s, 3H), 1.87 (d, 1H, J=9.3 Hz), 1.75 (d, 1H, J=9.3 Hz);LCMS: purity: 98%; MS (m/e): 248 (MH⁺).

B. 2-[(1S,4S)-5-Methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]-5-nitrotoluene(3.3 g) was dissolved in EtOH (50 mL) and transferred to Parrhydrogenation flask. Catalyst, Pd/C (450 mg), was added and the mixturesubjected to hydrogenation at 30 PSI for 2 h. The reaction mixture wasfiltered through Celite and the Celite filter cake washed with EtOH.Concentration of the combined filtrate provided3-methyl-4-[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]aniline,as a tan solid (2.52 g, 86%). ¹H NMR (DMSO-d₆): δ 6.58 (d, 1H, J=8.8Hz), 6.34 (s, 1H), 6.27 (d, 1H, J=8.8 Hz), 4.46 (s, 2H), 3.61 (s, 1H),3.24 (s, 1H), 3.16 (d, 1H, J=9.3 Hz), 2.93 (dd, 1H, J=1.8 and 9.3 Hz),2.61 (qt, 2H, J=9.3 Hz), 2.26 (s, 3H), 2.05 (s, 3H), 1.70 (d, 1H, J=9.1Hz), 1.63 (d, 1H, J=9.1 Hz). LCMS: purity: 97%; MS (m/e): 218 (MH⁺).

C. Alternatively, a heterogeneous mixture of(1S,4S)-2-methyl-2,5-diazabicyclo[2.2.1]heptane 2HBr salt (0.544 g, 2mmol), 2-fluoro-5-nitrotoluene (0.310 g, 2 mmol) and DIPEA (0.387 g, 6mmol) in NMP was refluxed for 2 days. The resulting residue was purifiedby column chromatography (silica gel, hexanes then 5-10% EtOAc inhexanes to afford2-[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]-5-nitrotoluene,which was reduced by hydrogenation (H₂, 10% Pd/C, MeOH, 40 PSI) toafford3-methyl-4-[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]aniline;LCMS: purity: 91%; MS (m/e): 218 (MH⁺).

D. Alternatively, (1S,4S)-2-Methyl-2,5-diazabicyclo[2.2.1]heptane.2HBr(24.8 g, 90.5 mmol), 2-fluoro-5-nitrotoluene (12.0 g, 77.3 mmol) andK₂CO₃ (43.7 g, 316.9 mmol) in 90 mL NMP were heated at 110° C. for 14 hby stirring. The reaction mixture was allowed to cool and quenched bypouring into water (500 mL). The contents were then stirred untilprecipitation was observed (3-4 h). The yellow solid formed wascollected by filtration. The resulting filter cake washed with water(700 mL) and dried under vacuum suction. The filter cake wasre-suspended in 10% EtOAc/hexanes (100 mL) as a slurry and then filteredto provide the desired material2-[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]-5-nitrotoluene(14.2 g, 74% based on nitrotoluene; 63% based on diazabicycloheptane)after drying; ¹H NMR (DMSO-d₆): δ 7.88-7.55 (m, 2H), 6.69 (d, 1H, J=8.8Hz), 4.37 (s, 1H), 3.64 (dd, 1H, J=2.0 and 9.9 Hz), 3.38-3.55 (m, 2H),2.81 (d, 1H, J=9.9 Hz), 2.65 (d, 1H, J=9.9 Hz), 2.33 (s, 3H), 2.23 (s,3H), 1.87 (d, 1H, J=9.3 Hz), 1.75 (d, 1H, J=9.3 Hz). LCMS: purity: 98%;MS (m/e): 248 (MH⁺).

E. 2-[(1S,4S)-5-Methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]-5-nitrotoluene(14.2 g), as prepared above in Paragraph D, was dissolved in EtOH (50mL), transferred to a Parr hydrogenation flask. Pd/C (1.5 g) wasintroduced to above flask and subjected to hydrogenation at 30 psi for 2h. The reaction mixture was filtered through Celite and the filter cakewas washed further with EtOH (300 mL). Concentration of the filtrateprovided3-Methyl-4-[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]aniline asa white-tan solid (11.7 g, 86%); ¹H NMR (DMSO-d₆): δ 6.58 (d, 1H, J=8.8Hz), 6.34 (s, 1H), 6.27 (d, 1H, J=8.8 Hz), 4.46 (s, 2H), 3.61 (s, 1H),3.24 (s, 1H), 3.16 (d, 1H, J=9.3 Hz), 2.93 (dd, 1H, J=1.8 and 9.3 Hz),2.61 (qt, 2H, J=9.3 Hz), 2.26 (s, 3H), 2.05 (s, 3H), 1.70 (d, 1H, J=9.1Hz), 1.63 (d, 1H, J=9.1 Hz). LCMS: purity: 97%; MS (m/e): 218 (MH⁺).

Synthetic Preparation 3 Compounds of Formula (D)4-(1,4-Diazabicyclo[3.2.2.]nonan-4-yl)-3-methylaniline

A. A mixture of 2-fluoro-5-nitrotoluene (1.08 g, 6.98 mmol),1,4-diazabicyclo[3.2.2]nonane (0.8 g, 6.34 mmol) and K₂CO₃ (2.2 g, 15.86mmol) in 8 mL of DMF was stirred at 100° C. for 16 h. After cooling toambient temperature, water (40 mL) was slowly added to the mixture. Theresulting (yellow) solid was filtered and washed three times with water.Thin layer chromatography showed trace amount of starting aryl fluoride.The solid 4-(2-methyl-4-nitrophenyl)-1,4-diazabicyclo[3.2.2]nonane wassuspended in 25 mL of Et₂O, sonicated for 10 min, collected byfiltration and washed with Et₂O; 950 mg; Purity (LC-MS): >97%; MS (m/e):262.4 (MH⁺).

B. 4-(2-Methyl-4-nitrophenyl)-1,4-diazabicyclo[3.2.2]nonane (950 m) wasdissolved in 30 mL of MeOH. Catalyst, 10% Pd—C (300 mg), was then added,and the mixture was hydrogenated at the atmosphere of H₂ (50 psi) for 1h. The reaction mixture was filtered through Celite and washed withMeOH. 4-(1,4-Diazabicyclo[3.2.2.]nonan-4-yl)-3-methylaniline wasobtained as a dark oil in quantitative yield; Purity (LC-MS): 97.48%; MS(m/e): 231.1 (MH⁺).

Synthetic Preparation 4 Compounds of Formula (Eb)1-[6-(Morpholin-4-yl)pyridin-3-yl)]ethanone

1-(6-chloro-3-pyridinyl)ethanone (20 g, 128.55 mmol) and morpholine (43mL, 43 g, 493 mmol) in ethanol (100 mL) were heated to reflux at 95° C.Upon consumption of 1-(6-chloro-3-pyridinyl)ethanone (18 h), thereaction mixture was cooled and concentrated to dryness. An ice-coldsolution of water (65 mL) was transferred to the above material, thensonicated for 10 min and stirred at 0° C. for a period of 2 h. The solidformed was collected by filtration and suction dried. Further workup ofthe solid by reslurrying in ice-cold solution of water (250 mL) andfiltration of the slurry provided 18.8 g (70%) of1-[6-(morpholin-4-yl)pyridin-3-yl)]ethanone as off-white tan solid aftervacuum drying; ¹H NMR (DMSO-d₆): δ 8.71 (d, 1H, J=2.4 Hz), 8.00 (dd, 1H,J=1.4 and 9.0 Hz), 6.86 (d, 1H, J=9.0 Hz), 2.44 (s, 3H). LCMS: purity:96%; MS (m/e): 207 (MH⁺).

Synthetic Preparation 5 Compounds of Formula (Ga)3-(3-(Dimethylamino)prop-2-en-1-onyl)-6-chloropyridine

A homogeneous mixture of 3-acetyl-6-chloropyridine (5 mL) (which can beprepared in a similar manner by the methods disclosed in Lee, C-H. etal., J. Med. Chem. (2001), Vol. 44, pp. 2133-2138) inN,N-dimethylformamide dimethylacetal (15 mL) was refluxed for 4 h. Aftercooling the reaction mixture to ambient temperature, it was diluted withhexanes (100 mL), sonicated for 30 seconds and the solid formed wasisolated by filtration. The resulting solid was then washed with hexanes(3×25 mL), dried and analyzed to afford3-(3-(dimethylamino)prop-2-en-1-onyl)-6-chloropyridine; LCMS: purity:92%; MS (m/e): 212 (MH⁺).

Synthetic Preparation 6 Compounds of Formula (Gb)3-[3-(Dimethylamino-2-propen-1-one)-6-(morpholin-4-yl)pyridine

1-[6-(morpholin-4-yl)pyridin-3-yl)]ethanone (18 g, 87.3 mmol) inN,N-dimethylformamide dimethylacetal (100 mL) was heated to reflux (110°C.) till complete consumption of1-[6-(morpholin-4-yl)pyridin-3-yl)]ethanone as determined by silica gelTLC and LC/MS. After 45 h, the heterogeneous reaction mixture was cooledto ambient temperature and the crude product collected by filtration.The filter cake was washed with Et₂O (75 mL) and dried under vacuum toprovide 18.0 g (78%) of3-[3-(dimethylamino-2-propen-1-one)-6-(morpholin-4-yl)pyridine; ¹H NMR(DMSO-d₆): δ 8.69 (d, 1H, J=2.4 Hz), 8.00 (dd, 1H, J=2.4 and 9.0 Hz),7.62 (d, 1H, J=12.3 Hz), 6.80 (d, 1H, J=9.0 Hz), 5.76 (d, 1H, J=12.3Hz), 3.68-3.65 (m 4H), 3.61-3.59 (m, 4H), 3.30 (s, 3H), 2.87 (s, 3H).LCMS: purity: 99%; MS (m/e): 262 (MH⁺)

Synthetic Preparation 7 Compounds of Formula (Ja)[3-methyl-4-((1S,4S)-2-methyl-2,5-diazabicyclo[2.2.1]heptan-5-yl)phenyl][N,N-bis(tert-butoxycarbonyl)]guanidine

A. Compound (Da),3-methyl-4-[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]aniline,(0.105 g, 0.6 mmol) and1-(tert-butoxycarbonylamino(tert-butoxycarbonylimino)methyl)pyrazole (H)(0.186 g, 0.6 mmol) were combined in DMF (2 mL) and stirred at ambienttemperature for 3 days. The reaction was monitored by LCMS. Thehomogenous reaction mixture was then diluted with water (20 mL), thesolid precipitate formed was isolated by filtration, and purified bycolumn chromatography (silica gel, CH₂Cl₂ then 2-5% MeOH in CH₂Cl₂) togive[3-methyl-4-((1S,4S)-2-methyl-2,5-diazabicyclo[2.2.1]heptan-5-yl)phenyl][N,N-bis(tert-butoxycarbonyl)]guanidine;LCMS: purity: 99%; MS (m/e): 460 (MH⁺).

B. On a larger scale,3-methyl-4-[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]aniline(10.0 g, 45.8 mmol) and1-(tert-butoxycarbonylamino(tert-butoxycarbonylimino)methyl)pyrazole(15.0 g, 48.2 mmol) were combined in DMF (25 mL) and stirred at ambienttemperature. The progress of homogenous reaction was monitored by LC/MS.After 36 h, the reaction mixture was added slowly to water (300 mL) in abeaker with vigorous stirring, whereupon a precipitate formed. Thereaction flask was rinsed with DMF (2×5 mL) and transferred to thebeaker. Suction filtration of the suspension, further washing of theresulting filter cake with water (200 mL) and air drying under suctionprovided 20.5 g (97%) of[3-methyl-4-((1S,4S)-2-methyl-2,5-diazabicyclo[2.2.1]heptan-5-yl)phenyl][N,N-bis(tert-butoxycarbonyl)]guanidine(Ja) as a off-white purple solid; LCMS: purity: 96%; MS (m/e): 449(MH⁺).

Synthetic Preparation 8 Compounds of Formula (Ka)[3-methyl-4-((1S,4S)-2-methyl-2,5-diazabicyclo[2.2.1]heptan-5-yl)phenyl]guanidine

A. A solution of[3-methyl-4-((1S,4S)-2-methyl-2,5-diazabicyclo[2.2.1]heptan-5-yl)phenyl][N,N-bis(tert-butoxycarbonyl)]guanidine(0.100 g) in CH₂Cl₂ (20 mL) with TFA (5 mL) was stirred at ambienttemperature for 4 h. The reaction progress was monitored by TLC (silicagel). The resulting mixture was concentrated and the lyophilized toafford[3-methyl-4-((1S,4S)-2-methyl-2,5-diazabicyclo[2.2.1]heptan-5-yl)phenyl]guanidine,as a TFA salt; LCMS: purity: 89%; MS (m/e): 260 (MH⁺).

B. Alternatively, TFA (80 mL) was added to a stirred solution of[3-methyl-4-((1S,4S)-2-methyl-2,5-diazabicyclo[2.2.1]heptan-5-yl)phenyl][N,N-bis(tert-butoxycarbonyl)]guanidine(20.2 g) in CH₂Cl₂ (80 mL) at 0° C. over a period of 30 min. Theice-bath was removed after 1 h and the reaction contents allowed tostir. Progress of the reaction mixture was monitored by LC/MS. Thereaction mixture was concentrated after complete conversion of thestarting material to[3-methyl-4-((1S,4S)-2-methyl-2,5-diazabicyclo[2.2.1]heptan-5-yl)phenyl]guanidine,dried overnight under high vacuum and used in the next step withoutfurther purification. LCMS: purity: 96%; Crude weight: 45.4 g, backcalculation provided approximately 34 g of total amount of TFA presentin the crude.

Synthetic Example 14-(6-(N,N-dimethylamino)pyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine

A. 2-Chloro-4-(6-dimethylaminopyridin-3-yl)pyrimidine (35 mg, 0.15 mmol)and3-methyl-4-[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]phenylamine(55 mg, 0.25 mmol) in 1.5 mL 2-propanol with TFA (4 drops) were heatedat 100° C. for 12 h in a sealed tube. Reaction progress was monitored byLC/MS. Upon completion, the reaction mixture was concentrated andpurified by preparative HPLC. The pure concentrate, obtained afterpurification, was exposed to aq. K₂CO₃ solution to neutralize any acidremaining. The solid formed upon exposure to aq. K₂CO₃ solution wascollected by filtration, washed with water and dried to provide4-(6-(N,N-dimethylamino)pyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,compound #1, as an off-white solid (35 mg, 56%). ¹H NMR (DMSO-d₆): δ9.13 (s, 1H), 8.81 (s, 1H), 8.31 (d, 1H, J=5.3 Hz), 8.20 (dd, 1H, J=2.3and 8.8 Hz), 7.49 (dd, 1H, J=2.3 and 8.8 Hz), 7.43 (s, 1H), 7.17 (d, 1H,J=5.3 Hz), 6.74 (d, 2H, J=8.8 Hz), 3.88 (s, 1H), 3.20 (app qt, 2H, J=9.0Hz), 3.09 (s, 6H), 2.71 (app qt, 2H, J=9.0 Hz), 2.27 (s, 3H), 2.19 (s,3H), 1.77 (d, 1H, J=9.0 Hz), 1.69 (d, 1H, J=9.0 Hz); LCMS: purity: 98%;MS (m/e): 416 (MH⁺).

B. Alternatively, a heterogeneous mixture of3-(3-(dimethylamino)prop-2-en-1-onyl)-6-chloropyridine (0.063 g, 0.75mmol) and[3-methyl-4-((1S,4S)-2-methyl-2,5-diazabicyclo[2.2.1]heptan-5-yl)phenyl]guanidineTFA salt (0.110 g, 0.75 mmol) with K₂CO₃ (0.051 g, 2.25 mmol) inisopropanol (1 mL) was shaken in a sealed tube at 100° C. in for 24 h.The formation of4-(6-(chloro)pyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-aminewas confirmed by LCMS. To this reaction vial 40% of aqueous solution ofMe₂NH.HCl solution (1 mL) was added and then heated in a sealed tube for3 h at 100° C. The resulting reaction mixture was purified by columnchromatography (silica gel; CH₂Cl₂ then 1% 2N NH₃/MeOH in CH₂Cl₂) toafford4-(6-(N,N-dimethylamino)pyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,compound #1; LCMS: purity: 99%; MS (m/e): 416 (MH⁺).

Synthetic Example 24-(6-(N,N-dimethylamino)pyridin-3-yl)-5-methyl-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine

Following substantially one of the procedures as described in SYNTHETICEXAMPLE 1 and making non-critical variations in the experimentalparameters and using the appropriately substituted starting materialsand reagents,4-(6-(N,N-dimethylamino)pyridin-3-yl)-5-methyl-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,compound #2, was obtained; ¹H NMR (DMSO-d₆): δ 9.04 (s, 1H), 8.48 (d,1H, J=1.8 Hz), 8.22 (s, 1H), 7.89 (dd, 1H, J=2.0 and 8.8 Hz), 7.45 (appd, 1H, J=8.8 Hz), 7.40 (s, 1H), 6.71 (t, 2H, J=8.8 Hz), 3.84 (s, 1H),3.18 (d, 1H, J=9.0 Hz), 3.11 (d, 1H, J=9.0 Hz), 3.08 (s, 6H), 2.72 (d,1H, J=9.0 Hz), 2.64 (d, 1H, J=9.0 Hz), 2.25 (s, 3H), 2.23 (s, 3H), 2.16(s, 3H), 1.75 (d, 1H, J=9.0 Hz), 1.67 (d, 1H, J=9.0 Hz); LCMS: purity:99%; MS (m/e): 430 (MH⁺).

Synthetic Example 34-(6-(N,N-dimethylamino)pyridin-3-yl)-5-trifluoromethyl-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine

Following substantially one of the procedures as described in SYNTHETICEXAMPLE 1 and making non-critical variations in the experimentalparameters and using the appropriately substituted starting materialsand reagents,4-(6-(N,N-dimethylamino)pyridin-3-yl)-5-trifluoromethyl-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,compound #3, was obtained; ¹H NMR (DMSO-d₆): δ 9.91 (s, 1H), 8.68 (s,1H), 8.34 (s, 1H), 7.74 (app d, 1H, J=8.8 Hz), 7.40-7.37 (m, 2H), 6.73(d, 1H, J=8.8 Hz), 6.71 (d, 1H, J=8.8 Hz), 3.90 (s, 1H), 3.18 (s, 2H),3.08 (s, 6H), 2.72 (d, 1H, J=9.0 Hz), 2.65 (d, 1H, J=9.0 Hz), 2.25 (s,3H), 2.17 (s, 3H), 1.77 (d, 1H, J=9.0 Hz), 1.67 (d, 1H, J=9.0 Hz); LCMS:purity: 99%; MS (m/e): 484 (MH⁺).

Synthetic Example 44-(6-(N,N-dimethylamino)pyridin-3-yl)-5-fluoro-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine

Following substantially one of the procedures as described in SYNTHETICEXAMPLE 1 and making non-critical variations in the experimentalparameters and using the appropriately substituted starting materialsand reagents,4-(6-(N,N-dimethylamino)pyridin-3-yl)-5-fluoro-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,compound #4, was obtained; ¹H NMR (DMSO-d₆): δ 9.23 (s, 1H), 8.80 (s,1H), 8.40 (d, 1H, J=4.1 Hz), 8.15 (app d, 1H, J=9.1 Hz), 7.43-7.38 (m,2H), 6.79 (d, 1H, J=9.1 Hz), 6.73 (d, 1H, J=8.8 Hz), 3.87 (s, 1H), 3.21(d, 1H, J=9.0 Hz), 3.17 (d, 1H, J=9.0 Hz), 3.10 (s, 6H), 2.72 (d, 1H,J=9.0 Hz), 2.66 (d, 1H, J=9.0 Hz), 2.26 (s, 3H), 2.18 (s, 3H), 1.76 (d,1H, J=9.0 Hz), 1.67 (d, 1H, J=9.0 Hz); LCMS: purity: 99%; MS (m/e): 434(MH⁺).

Synthetic Example 54-(6-(N,N-dimethylamino)pyridin-3-yl)-5-fluoro-N-(3-fluoro-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine

Following substantially one of the procedures as described in SYNTHETICEXAMPLE 1 and making non-critical variations in the experimentalparameters and using the appropriately substituted starting materialsand reagents,4-(6-(N,N-dimethylamino)pyridin-3-yl)-5-fluoro-N-(3-fluoro-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,compound #5, was obtained; ¹H NMR (DMSO-d₆): δ 9.45 (s, 1H), 8.80 (s,1H), 8.44 (d, 1H, J=1.4 and 9.0 hz), 7.58 (dd, 1H, J=9.1 and 16 Hz),7.29 (d, 1H, J=8.8 hz), 6.80 (d, 1H, J=9.1H), 6.68 (app t, 1H, J=9.3Hz), 4.15 (s, 1H), 3.39 (d, 1H, J=9.0 Hz), 3.16 (d, 1H, J=9.0 Hz), 3.11(s, 6H), 2.72 (d, 1H, J=9.1 Hz), 2.59 (d, 1H, J=9.0 Hz), 2.23 (s, 3H),1.80 (d, 1H, J=9.0 Hz), 1.69 (d, 1H, J=9.0 Hz); LCMS: purity: 98%; MS(m/e): 438 (MH⁺).

Synthetic Example 64-(6-(N,N-dimethylamino)pyridin-3-yl)-5-methyl-N-(3-fluoro-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine

Following substantially one of the procedures as described in SYNTHETICEXAMPLE 1 and making non-critical variations in the experimentalparameters and using the appropriately substituted starting materialsand reagents,4-(6-(N,N-dimethylamino)pyridin-3-yl)-5-methyl-N-(3-fluoro-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,compound #6, was obtained; ¹H NMR (DMSO-d₆): δ 9.27 (s, 1H), 8.49 (d,1H, J=2.3 Hz), 8.26 (s, H), 7.88 (d, 1H, J=2.3 and 8.8 Hz), 7.66 (d, 1H,J=2.3 and 16.8 Hz), 7.31 (d, 1H, J=8.8 Hz), 6.73 (d, 1H, J=8.8 Hz), 6.65(app t, 1H, J=10.0 Hz), 4.13 (s, 1H), 3.37 (app d, 1H, J=9.0 Hz), 3.15(dd, 1H, J=2.6 and 9.0 Hz), 3.08 (s, 6H), 2.70 (d, 1H, J=9.0 Hz), 2.59(d, 1H, J=9.0 Hz), 2.24 (s, 3H), 2.23 (s, 3H), 1.79 (d, 1H, J=9.0 Hz),1.69 (d, 1H, J=9.0 Hz); LCMS: purity: 98%; MS (m/e): 434 (MH⁺).

Synthetic Example 74-(6-(N,N-dimethylamino)pyridin-3-yl)-N-(3-fluoro-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine

Following substantially one of the procedures as described in SYNTHETICEXAMPLE 1 and making non-critical variations in the experimentalparameters and using the appropriately substituted starting materialsand reagents,4-(6-(N,N-dimethylamino)pyridin-3-yl)-N-(3-fluoro-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,compound #7, was obtained; ¹H NMR (DMSO-d₆): δ 9.36 (s, 1H), 8.88 (s,1H), 8.35 (d, 1H, J=5.3 Hz), 8.19 (dd, 1H, J=2.3 and 8.8 Hz), 7.64 (d,1H, J=2.3 and 16.8 Hz), 7.35 (d, 1H, J=8.2 Hz), 7.22 (d, 1H, J=5.3 Hz),6.75 (d, 1H, J=9.1 Hz), 6.65 (app t, 1H, J=9.0 Hz), 4.16 (s, 1H), 3.39(app d, 1H, J=9.0 Hz), 3.18 (app d, 1H, J=9.0 Hz), 3.10 (s, 6H), 2.72(d, 1H, J=9.1 Hz), 2.59 (d, 1H, J=9.0 Hz), 2.23 (s, 3H), 1.79 (d, 1H,J=9.0 Hz), 1.69 (d, 1H, J=9.0 Hz); LCMS: purity: 98%; MS (m/e): 420(MH⁺).

Synthetic Example 84-(4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine

Following substantially one of the procedures as described in SYNTHETICEXAMPLE 1 and making non-critical variations in the experimentalparameters and using the appropriately substituted starting materialsand reagents,4-(4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,compound #8, was obtained; ¹H NMR (DMSO-d₆): δ 9.13 (s, 1H), 8.49 (apps, 1H), 8.31 (d, 1H, J=5.3 Hz), 7.70 (app s, 1H), 7.45 (app s, 2H), 7.16(d, 1H, J=5.3 Hz), 6.73 (d, 1H, J=8.4 Hz), 4.22 (m, 2H), 3.88 (s, 1H),3.51 (s, 2H), 3.19 (d, 1H, J=9.5 Hz), 3.14 (app d, 1H, J=9.5 Hz), 3.10(s, 6H), 2.72 (d, 1H, J=9.5 Hz), 2.65 (d, 1H, J=9.5 Hz), 2.26 (s, 3H),2.18 (s, 3H), 1.76 (d, 1H, J=9.0 Hz), 1.69 (d, 1H, J=9.0 Hz); LCMS:purity: 98%; MS (m/e): 444 (MH⁺).

Synthetic Example 94-(4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(3-fluoro-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine

Following substantially one of the procedures as described in SYNTHETICEXAMPLE 1 and making non-critical variations in the experimentalparameters and using the appropriately substituted starting materialsand reagents,4-(4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(3-fluoro-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,compound #9, was obtained; ¹H NMR (DMSO-d₆): δ 9.34 (s, 1H), 8.51 (d,1H, J=0.9 Hz), 8.35 (d, 1H, J=5.3 Hz), 7.67 (d, 1H, J=17.4 Hz), 7.60 (d,1H, J=0.9 Hz), 7.31 (d, 1H, J=8.2 Hz), 7.20 (d, 1H, J=5.3 Hz), 6.68 (appt, 1H, J=9.5 Hz), 4.23-4.21 (m, 2H), 4.16 (s, 1H), 3.53-3.50 (m, 2H),3.39 (d, 1H, J=9.6 Hz), 3.17 (d, 1H, J=9.6 Hz), 3.11 (s, 3H), 2.72 (d,1H, J=9.6 Hz), 2.59 (d, 1H, J=9.6 Hz), 2.23 (s, 3H), 1.77 (d, 1H, J=9.4Hz), 1.69 (d, 1H, J=9.4 Hz); LCMS: purity: 98%; MS (m/e): 448 (MH⁺).

Synthetic Example 104-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine

A. Following substantially one of the procedures as described inSYNTHETIC EXAMPLE 1 and making non-critical variations in theexperimental parameters and using the appropriately substituted startingmaterials and reagents,4-(6-1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,compound #10, was obtained; ¹H NMR (DMSO-d₆): δ 9.19 (s, 1H), 8.91 (d,1H, J=0.9 Hz), 8.35 (d, 1H, J=5.3 Hz), 8.26 (d, 1H, J=9.1 Hz), 7.48-7.44(m, 2H), 7.20 (d, 1H, J=5.3 Hz), 6.95 (d, 1H, J=9.1 Hz), 3.66-3.63 (m,4H), 3.55-3.53 (m, 4H), 3.19 (d, 1H, J=8.8 Hz), 3.17 (d, 1H, J=8.8 Hz),2.70 (d, 1H, J=9.1 Hz), 2.68 (d, 1H, J=9.1 Hz), 2.27 (s, 3H), 2.18 (s,3H), 1.77 (d, 1H, J=9.1 Hz), 1.69 (d, 1H, J=9.1 Hz); LCMS: purity: 98%;MS (m/e): 459 (MH⁺).

B. Alternatively,[3-methyl-4-((1S,4S)-2-methyl-2,5-diazabicyclo[2.2.1]heptan-5-yl)phenyl]guanidineTFA salt (45.4 g) was dissolved in 2-propanol (200 mL) and basified with40 g of solid K₂CO₃ in portions. The pH was measured by diluting therespective aliquots with water drawn upon base addition [20 g (pH 5), 25g (pH 7), 33 g (pH 9) and 40 g (pH 10)].3-[3-(Dimethylamino-2-propen-1-one)-6-(morpholin-4-yl)pyridine (10.5 g,40.1 mmol) and additional 2-propanol (100 mL) were transferred to theabove off-white basified guanidine heterogeneous mixture and heated toreflux at 120° C. Progress of the reaction was monitored by LC/MS.Analysis of the reaction after 96 h provided 23%, 6% and 67% of theguanidine, the enamine and the desired product, respectively. Theresulting pale yellow heterogeneous mixture was cooled to ambienttemperature and diluted with water (200 mL). The pale yellow solidformed upon stirring was filtered to provide 10.2 g of crude product.The collected solid was suspended in water and filtered to provide 8.8 g(47%) of4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amineas a pale yellow powder upon drying, compound #10, ¹H NMR (DMSO-d₆): δ9.19 (s, 1H), 8.91 (d, 1H, J=0.9 Hz), 8.35 (d, 1H, J=5.3 Hz), 8.26 (d,1H, J=9.1 Hz), 7.48-7.44 (m, 2H), 7.20 (d, 1H, J=5.3 Hz), 6.95 (d, 1H,J=9.1 Hz), 3.66-3.63 (m, 4H), 3.55-3.53 (m, 4H), 3.19 (d, 1H, J=8.8 Hz),3.17 (d, 1H, J=8.8 Hz), 2.70 (d, 1H, J=9.1 Hz), 2.68 (d, 1H, J=9.1 Hz),2.27 (s, 3H), 2.18 (s, 3H), 1.77 (d, 1H, J=9.1 Hz), 1.69 (d, 1H, J=9.1Hz); LCMS: purity: 98%; MS (m/e): 458 (MH⁺).

Synthetic Example 114-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-fluoro-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine

Following substantially one of the procedures as described in SYNTHETICEXAMPLE 1 and making non-critical variations in the experimentalparameters and using the appropriately substituted starting materialsand reagents,4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-fluoro-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,compound #11, was obtained; ¹H NMR (DMSO-d₆): δ 9.40 (s, 1H), 8.91 (s,1H), 8.38 (d, 1H, J=5.3 Hz), 8.24 (d, 1H, J=8.8 Hz), 7.67 (d, 1H, J=16.4Hz), 7.34 (d, 1H, J=8.2 Hz), 7.25 (d, 1H, J=5.3 Hz), 6.96 (d, 1H, J=9.1Hz), 6.68 (app t, 1H, J=9.9 Hz), 4.16 (s, 1H), 3.69-3.67 (m, 4H),3.58-3.57 (m, 4H), 3.41 (d, 1H, J=9.1 Hz), 3.17 (d, 1H, J=9.1 Hz), 2.72(d, 1H, J=9.1 Hz), 2.59 (d, 1H, J=9.1 Hz), 2.23 (s, 3H), 1.79 (d, 1H,J=8.8 Hz), 1.69 (d, 1H, J=8.8 Hz); LCMS: purity: 99%; MS (m/e): 462(MH⁺).

Synthetic Example 12

In a similar manner as described above utilizing the appropriatelysubstituted starting materials and reagents, the following compounds offormula (Ia) were prepared:

-   4-(4-(N,N-dimethylamino)phenyl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #14, ¹H NMR (DMSO-d₆): δ 9.09 (s, 1H), 8.28 (d, 1H, J=5.4    Hz), 8.00 (d, 2H, J=8.4 Hz), 7.48 (bs, 2H), 7.13 (d, 1H, J=5.4 Hz),    6.78 (d, 2H, J=8.7 Hz), 6.73 (d, 1H, J=9.6 Hz), 3.87 (s, 1H), 3.17    (m, 2H), 2.98 (s, 6H), 2.69 (m, 2H), 2.26 (s, 3H), 2.19 (s, 3H),    1.76 (d, 1H, J=9.3 Hz), 1.68 (d, 1H, J=9.3 Hz); LCMS: purity: 99%;    MS (m/e): 415 (MH⁺);-   4-(4-(N,N-dimethylamino)phenyl)-N-(3-fluoro-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #15, ¹H NMR (DMSO-d₆): δ 9.33 (s, 1H), 8.32 (d, 1H, J=5.1    Hz), 7.99 (d, 2H, J=9.0 Hz), 7.72 (d, 1H, J=16.5 Hz), 7.36 (d, 1H,    J=8.7 Hz), 7.18 (d, 1H, J=5.1 Hz), 6.74 (m, 3H), 4.21 (s, 1H), 3.47    (m, 2H), 3.21 (m, 1H), 2.99 (s, 6H), 2.80 (bs, 2H), 2.34 (s, 3H),    1.87 (d, 1H, J=8.7 Hz), 1.77 (d, 1H, J=8.7 Hz); LCMS: purity: 99%;    MS (m/e): 419 (MH⁺);-   4-(6-(4-acetylpiperazin-1-yl)pyridin-3-yl)-N-(3-fluoro-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #16, ¹H NMR (DMSO-d₆): δ 9.40 (s, 1H), 8.91 (s, 1H), 8.37    (d, 1H, J=5.4 Hz), 8.24 (d, 1H, J=8.7 Hz), 7.66 (d, 1H, J=16.2 Hz),    7.34 (d, 1H, J=9.3 Hz), 7.25 (d, 1H, J=5.1 Hz), 6.97 (d, 1H, J=9.0    Hz), 6.68 (t, 1H, J=9.6 Hz, J=9.8 Hz), 4.16 (s, 1H), 3.59 (m, 8H),    3.40 (m, 1H), 3.16 (m, 1H), 2.72 (d, 1H, J=9.6 Hz), 2.58 (d, 1H,    J=9.6 Hz), 2.23 (s, 3H), 2.03 (s, 3H), 1.79 (d, 1H, J=9.3 Hz), 1.69    (d, 1H, J=9.3 Hz); LCMS: purity: 99%; MS (m/e): 503 (MH⁺);-   4-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(3-fluoro-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #19, ¹H NMR (CD₃OD, 300 MHz) 8.68 (m, 1H), 8.41 (m, 2H),    7.99 (m, 1H), 7.68 (m, 1H), 7.25 (m, 2H), 6.80 (m, 1H), 4.57 (s,    1H), 4.27 (s, 1H), 3.80 (m, 2H), 4.46 (m, 1H), 3.24 (s, 1H), 2.93    (s, 3H), 2.66 (m, 3H), 2.30 (m, 2H), 1.55 (s, 6H); MS (ES) 476.19    (M+H);-   4-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #20, ¹H NMR (CD₃OD, 300 MHz) 8.68 (m, 1H), 8.48 (s, 1H),    8.38 (m, 1H), 8.00 (m, 1H), 7.49 (m, 2H), 7.21 (m, 1H), 6.96 (m,    1H), 4.23 (m, 2H), 3.74 (m, 1H), 3.50 (m, 2H), 3.24 (d, 1H), 2.94    (s, 3H), 2.65 (m, 1H), 2.32 (s, 3H), 2.89 (m, 2H), 1.54 (s, 6H); MS    (ES) 472.22 (M+H);-   4-(1H-indol-6-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #21, ¹H NMR (300 MHz, CDCl₃): δ 10.26 (b, 1H), 8.36-8.34    (m, 1H), 8.20 (b, 1H), 7.79-7.76 (d, J=8.8 Hz, 1H), 7.67-7.64 (d,    J=8.8 Hz, 1H), 7.79-7.41 (m, 3H), 7.31 (b, 1H), 7.13-7.12 (m, 1H),    6.81-6.79 (d, J=9 Hz, 1H), 6.51 (b, 1H), 3.93 (s, 1H), 3.42-3.39 (m,    1H), 3.20-3.17 (d, J=9.9 Hz, 1H), 2.91-2.82 (m, 1H), 2.69 (s, 4H),    2.41 (s, 3H), 2.31 (s, 3H); LCMS: purity: 99%; MS (m/z); 411 (M+H)⁺;-   4-(1H-pyrrolo[2,3-b]pyridin-5-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #22, ¹H NMR (300 MHz, CDCl₃): δ 9.10-9.03 (m, 2H), 8.61 (s,    1H), 8.41-8.40 (d, J=5.2 Hz, 1H), 7.45-7.35 (m, 3H), 7.14-7.13 (d,    J=4.1 Hz, 1H), 7.01 (s, 1H), 6.83-6.81 (d, J=8.8 Hz, 1H), 6.60 (b,    1H), 3.95 (b, 1H), 3.46-3.43 (m, 2H), 3.22-3.19 (d, J=9.6 Hz, 1H),    2.96-2.84 (m, 2H), 2.44 (s, 3H), 2.33 (s, 3H), 1.96-1.86 (m, 2H);    LCMS: purity; 100%; MS (m/z); 412 (M+H)⁺;-   4-(1H-pyrrolo[2,3-b]pyridin-5-yl)-N-(3-fluoro-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #23, ¹H NMR (300 MHz, d₆-DMSO): δ 11.86 (b, 1H), 9.55-9.46    (b, 2H), 8.97 (s, 1H), 8.64 (s, 1H), 8.44-8.42 (d, J=5.2 Hz, 1H),    7.52-7.39 (m, 3H), 6.85 (t, J=18.7 Hz, 1H), 6.52 (s, 1H), 4.5 (b,    1H), 4.23 (b, 1H), 3.70-3.58 (m, 2H), 3.33-3.29 (b, 1H), 3.06-3.03    (b, 1H), 2.82 (b, 3H), 2.33-2.29 (m, 1H), 2.09-2.05 (m, 1H); LCMS;    purity; 100%; MS (m/z); 416 (M+H)⁺;-   4-(6-(dimethylamino)pyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-ethyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #24, ¹H NMR (300 MHz, CDCl₃): δ 8.86 (s, 1H), 8.30 (dd,    J=1.3 and 1.6 Hz, 1H), 8.16-8.13 (d, J=9.0 Hz, 1H), 7.47-7.44 (d,    J=9.0 Hz, 1H), 6.96-6.94 (m, 1H), 6.87 (s, 1H), 6.80-6.78 (d, J=7.9    Hz, 1H), 6.58-6.55 (d, J=8.8 Hz, 1H), 3.95 (s, 1H), 3.53 (s, 1H),    3.42-3.39 (m, 1H), 3.17 (s, 6H), 3.00-2.97 (d, J=9.6 Hz, 1H),    2.79-2.76 (d, J=9.4 Hz, 1H), 2.63-2.51 (m, 1H), 2.30 (s, 3H),    1.93-1.85 (m, 2H), 1.59 (b, 2H), 1.11-1.06 (m, 3H); LCMS: purity;    100%; MS (m/z); 430 (M+H)⁺;-   4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-ethyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #25, ¹H NMR (300 MHz, CDCl₃): δ 8.86 (s, 1H), 8.33-8.31 (d,    J=5.2 Hz, 1H), 8.19-8.17 (d, J=8.8 Hz, 1H), 7.44-7.41 (d, J=8.8 Hz,    1H), 7.23 (s, 1H), 6.97-6.90 (m, 2H), 6.80-6.77 (d, J=8.5 Hz, 1H),    6.69-6.66 (d, J=8.5 Hz, 1H), 3.95 (s, 1H), 3.82-3.81 (m, 4H),    3.64-3.61 (m, 5H), 3.43-3.40 (d, J=9.1 Hz, 1H), 3.21-3.17 (d, J=9.1    Hz, 1H), 3.01-2.98 (d, J=8.8 Hz, 1H), 2.80-2.78 (d, J=8.5 Hz, 1H),    2.64-2.57 (m, 2H), 2.30 (s, 3H), 1.91-1.89 (m, 2H), 1.12-1.07 (m,    3H); LCMS: purity; 98%; MS (m/z); 472 (M+H)⁺;-   4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-((ethylamino)carbonyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #26, ¹H NMR (300 MHz, CDCl₃): δ 8.86 (s, 1H), 8.33 (dd,    J=1.3 and 1.3 Hz, 1H), 8.19 (d, J=9.4 Hz, 1H), 7.47 (d, J=8.5 Hz,    1H), 7.29, (s, 1H), 6.98 (d, J=6.6 Hz, 1H), 6.91-6.79 (m, 2H), 6.69    (d, J=9.1 Hz, 1H), 4.64 (s, 1H), 4.15 (s, 1H), 4.04 (s, 1H), 3.82    (d, J=3.5 Hz, 4H), 3.64-3.61 (m, 4H), 3.52 (d, J=7.9 Hz, 1H),    3.44-3.24 (m, 3H), 2.28 (s, 3H), 2.03 (d, J=9.9 Hz, 1H), 1.88 (d,    J=8.8 Hz, 1H), 1.56 (b, 2H), 1.16-1.11 (m, 3H); LCMS: purity: 96%;    MS (m/z); 515 (M+H)⁺;-   4-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(3-methyl-4-((1S,4S)-5-oxa-2-azabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #27, ¹H NMR (300 MHz, d₆-DMSO): δ 9.22 (s, 1H), 8.64-8.62    (m, 1H), 8.36 (d, J=5.2 Hz, 1H), 7.77 (s, 1H), 7.48-7.41 (m, 3H),    7.23 (d, J=4.9 Hz, 1H), 6.82-6.77 (m, 1H), 4.52 (s, 1H), 4.12 (s,    1H), 3.90-3.87 (d, J=7.1 Hz, 1H), 3.71 (d, J=5.7 Hz, 1H), 3.07-3.02    (m, 1H), 2.18 (s, 3H), 1.88-1.73 (m, 1H), 1.38-1.35 (m, 8H); LCMS:    purity; 99%: MS (m/z); 459 (M+H)⁺;-   4-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(3-methyl-4-((1S,4S)-5-(ethylcarbonyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #28, ¹H NMR (300 MHz, d₆-DMSO): δ 9.31 (s, 1H), 8.68 (s,    1H), 8.41-8.39 (m, 1H), 7.92 (s, 1H), 7.49-7.40 (m, 2H), 7.30 (d,    J=5.2 Hz, 1H), 6.83 (t, J=15.9 Hz, 1H), 4.68 (b, 1H), 4.18 (d,    J=19.5 Hz, 1H), 3.51-3.38 (m, 2H), 3.14-3.05 (m, 1H), 2.19 (s, 6H)    1.93-1.77 (m, 2H), 1.42 (s, 6H), 0.99-0.92 (m, 3H); LCMS: purity;    99%; MS (m/z); 514 (M+H)⁺;-   4-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(3-methyl-4-((1S,4S)-5-(methylsulfonyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #29, ¹H NMR (300 MHz, d₆-DMSO): δ 11.47 (s, 1H), 9.36 (s,    1H), 8.73 (t, J=3.3 Hz, 1H), 8.45 (m, 1H), 8.01 (s, 1H), 7.51 (s,    1H), 7.45 (d, J=8.5 Hz, 1H), 7.34-7.32 (m, 1H), 6.88 (d, J=6.8 Hz,    1H), 4.33 (s, 1H), 4.15 (s, 1H), 3.41-3.22 (m, 4H), 2.96 (d, J=1.6    Hz, 3H), 2.21 (d, J=1.9 Hz, 3H), 1.92-1.80 (m, 2H), 1.45 (s, 6H);    LCMS: purity; 99%; MS (m/z); 536 (M+H)⁺;-   4-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(3-methyl-4-((1S,4S)-5-ethyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #30, ¹H NMR (300 MHz, CDCl₃): δ 8.64 (s, 1H), 8.39 (d,    J=3.8 Hz, 1H), 8.06 (s, 1H), 7.87 (s, 1H), 7.46-7.38 (m, 2H), 7.00    (d, J=4.1 Hz, 1H), 6.79 (d, J=8.26 Hz, 1H), 3.94 (b, 1H), 3.53 (b,    1H), 3.39 (d, J=9.3 Hz, 1H), 3.22 (d, J=9.0 Hz, 1H), 2.94 (b, 4H),    2.29 (s, 3H), 1.89 (d, J=6.6 Hz, 2H), 1.54 (s, 6H), 1.09 (m, 3H);    LCMS: purity; 98%; MS (m/z); 486 (M+H)⁺;-   4-(3′-oxo-3,4′-dihydrospiro[cyclobutane-1,2′-pyrido[3,2-b][1,4]oxazine]-7-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #31, ¹H NMR (300 MHz, CDCl₃): δ 8.63 (s, 1H), 8.39 (d,    J=5.2 Hz, 1H), 7.92 (s, 1H), 7.72 (s, 1H), 7.45-7.36 (m, 3H), 7.00    (d, J=4.9 Hz, 1H), 6.81 (d, J=8.2 Hz, 1H), 3.94 (s, 1H), 3.41 (d,    J=4.9 Hz, 2H), 3.22 (d, J=8.5 Hz, 1H), 2.93-2.82 (m, 3H), 2.67 (b,    4H), 2.41-2.26 (m, 6H), 2.01-1.84 (m, 3H); LCMS: purity; 95%; MS    (m/z); 484 (M+H)⁺;-   4-(3′-oxo-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrido[3,2-b][1,4]oxazine]-7′-yl)-N-(3-methyl-4-((1S,4S)-5-ethyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #32, ¹H NMR (300 MHz, CDCl₃): δ 8.63 (s, 1H), 8.39 (d,    J=4.9 Hz, 1H), 7.96 (d, J=13.7 Hz, 2H), 7.49-7.37 (m, 2H), 7.00 (d,    J=5.2 Hz, 1H) 6.79 (d, J=8.2 Hz, 1H), 3.94 (s, 1H), 3.53 (s, 1H),    3.39 (d, J=9.0 Hz, 1H), 3.22 (d, J=9.0 Hz, 1H), 2.98 (d, J=9.3 Hz,    2H), 2.80 (d, J=9.3 Hz, 1H), 2.66-2.51 (m, 5H), 2.37-2.25 (m, 5H),    2.03-1.84 (m, 3H), 1.09 (t, J=13.7 Hz, 3H); LCMS; purity; 97%; MS    (m/z); 498 (M+H)⁺;-   4-(1H-pyrrolo[2,3-b]pyridin-5-yl)-N-(3-methyl-4-((1S,4S)-5-oxa-2-azabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #33, ¹H NMR (300 MHz, d₆-DMSO): δ 9.30 (s, 1H), 9.01 (d,    J=1.6 Hz, 1H), 8.67 (s, 1H), 8.43 (d, J=5.2 Hz, 1H), 7.55-7.50 (m,    2H), 6.84 (d, J=8.5 Hz, 1H), 6.56 (d, J=3.3 Hz, 1H), 4.52 (s, 1H),    4.14 (s, 1H), 3.92 (d, J=7.1 Hz, 2H), 3.73 (d, J=5.7 Hz, 2H), 3.08    (d, J=9.3 Hz, 1H), 2.21 (s, 3H), 1.90-1.78 (m, 2H); LCMS: purity    95%; MS (m/z); 399 (M+H)⁺;-   4-(1H-pyrrolo[2,3-b]pyridin-5-yl)-N-(3-methyl-4-((1S,4S)-5-(2,2,2-trifluoroethyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #34, ¹H NMR (300 MHz, d₆-DMSO): δ 9.30 (s, 1H), 9.02 (t,    J=9.6 Hz, 1H), 8.68 (t, J=9.9 Hz, 1H), 8.43 (t, J=5.2 Hz, 1H), 7.55    (m, 4H), 7.38 (m, 1H), 6.80 (d, J=8.8 Hz, 1H), 6.57-6.52 (m, 1H),    3.96-2.85 (m, 7H), 2.22-2.19 (m, 4H), 1.77 (b, 2H); LCMS: purity;    96%; MS (m/z); 480 (M+H)⁺;-   4-(1H-pyrrolo[2,3-b]pyridin-5-yl)-N-(3-methyl-4-((1S,4S)-5-(cyclopropyl)methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #35, ¹H NMR (300 MHz, d₆-DMSO): δ 9.18 (b, 1H), 8.95 (t,    J=8.2 Hz, 1H), 8.59 (d, J=1.9 Hz, 1H), 8.33 (d, J=5.2 Hz, 1H),    7.46-7.37 (m, 4H), 7.28 (d, J=5.5 Hz, 1H), 6.68 (d, J=8.5 Hz, 1H),    6.47 (d, J=3.5 Hz, 1H), 3.82 (b, 1H), 2.81 (d, J=7.4 Hz, 1H), 2.62    (d, J=8.8 Hz, 1H), 2.41 (b, 2H), 2.27 (d, J=6.3 Hz, 2H), 2.13 (s,    3H), 1.65-1.63 (m, 3H), 0.71 (b, 1H), 0.33-0.30 (m, 2H), 0.00-01 (m,    2H); LCMS: purity; 95%; MS (m/z); 452 (M+H)⁺;-   4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-(2,2,2-trifluoroethyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #36, ¹H NMR (300 MHz, d₆-DMSO): δ 9.21 (b, 1H), 8.90 (b,    1H), 8.37-8.34 (m, 1H), 8.25 (d, J=6.6 Hz, 1H), 7.46 (b, 2H),    7.24-7.20 (m, 1H), 6.98-6.93 (m, 1H), 6.79-6.74 (m, 1H), 3.95 (b,    1H), 3.70 (b, 4H), 3.57 (b, 4H), 2.97 (b, 2H), 2.87-2.84 (m, 2H),    2.21-2.20 (m, 5H), 1.77 (b, 3H); LCMS: purity; 99%; MS (m/z); 526    (M+H)⁺;-   4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-(cyclopropyl)methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #37, ¹H NMR (300 MHz, d₆-DMSO): δ 9.18 (b, 1H), 8.89 (b,    1H), 8.35-8.22 (m, 2H), 7.46-7.42 (d, J=12.1 Hz, 2H), 7.21-7.19 (m,    1H), 6.95 (d, J=9.0 Hz, 1H), 6.72 (d, J=7.9 Hz, 1H), 3.88 (b, 1H),    3.68 (b, 4H), 3.57 (b, 4H), 3.15 (s, 2H), 2.87 (d, J=8.8 Hz, 1H),    2.69 (d, J=9.3 Hz, 1H), 2.48 (b, 1H), 2.34 (d, J=5.7 Hz, 2H), 2.18    (s, 3H), 1.71 (d, J=6.3 Hz, 2H), 0.78 (b, 1H), 0.40 (t, J=7.7 Hz,    2H), 0.06 (b, 2H); LCMS: purity; 98%; MS (m/z); 498 (M+H)⁺;-   4-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(3-methyl-4-((1S,4S)-5-(aminosulfonyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #38, ¹H NMR (300 MHz, d₆-DMSO): δ 11.50 (d, J=7.7 Hz, 1H),    9.47 (b, 1H), 8.73 (d, J=6.33 Hz, 1H), 8.46 (t, J=13.2 Hz, 1H), 8.02    (d, J=7.1 Hz, 1H), 7.53-7.33 (m, 4H), 6.94 (b, 3H), 4.23 (d, J=7.7    Hz, 2H), 3.37 (m, 4H), 1.92-1.85 (m, 2H), 1.47-1.38 (m, 8H); LCMS;    purity; 100%; MS (m/z); 537 (M+H)⁺;-   4-(3-fluoro-2-(morpholin-4-yl)pyridin-4-yl)-N-(3-fluoro-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #39, ¹H NMR (DMSO-d₆): δ 9.68 (s, 1H), 8.55 (dd, 1H, J=1.4    and 4.9 Hz), 8.15 (d, 1H, J=4.9 Hz), 7.62 (d, 1H, J=15.4 Hz),    7.31-7.28 (m, 2H), 7.15-7.14 (m, 1H), 6.67 (t, 1H, J=9.1 Hz), 4.15    (s, 1H), 3.73-3.71 (m, 4H), 3.39-3.37 (m, 5H), 3.15 (app d, 1H,    J=6.1 Hz), 2.70 (d, 1H, J=9.0 Hz), 2.57 (d, 1H, J=9.0 Hz), 2.22 (s,    3H), 1.79 (d, 1H, J=9.0 Hz), 1.68 (d, 1H, J=9.0 Hz); LCMS: purity:    99%; MS (m/e): 480 (MH⁺);-   4-(2-(morpholin-4-yl)pyrimidin-5-yl)-N-(4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #40, ¹H NMR (CD₃OD, 300 MHz): δ 9.02 (s, 2H), 8.26 (d, 1H),    7.45 (d, 2H), 7.08 (d, 1H), 6.63 (d, 2H), 4.31 (s, 1H), 3.89 (m,    4H), 3.75 (m, 4H), 3.45 (m, 2H), 2.81 (m, 2H), 2.65 (m, 2H), 2.39    (m, 2H), 2.37 (s, 3H), 1.98 (m, 2H); LCMS (m/z): 445.54 (MH⁺);-   4-(2-(morpholin-4-yl)pyrimidin-5-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #41, ¹H NMR (CD₃OD, 300 MHz): δ 9.02 (s, 2H), 8.54 (s, 1H),    8.29 (d, 1H), 7.38 (m, 1H), 7.08 (d, 1H), 6.87 (d, 1H), 4.00 (s,    1H), 3.89 (m, 4H), 3.75 (m, 4H), 3.56 (m, 1H), 3.42 (m, 1H), 3.25    (m, 1H), 3.04 (m, 1H), 2.86 (m, 1H), 2.65 (m, 1H), 2.49 (s, 3H),    2.29 (m, 3H), 1.96 (m, 2H); LCMS (m/z): 459.57 (MH⁺);-   4-(2-(morpholin-4-yl)pyrimidin-5-yl)-N-(3-methyl-4-((1S,4S)-5-oxa-2-azabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #42, ¹H NMR (CD₃OD, 300 MHz): δ 9.02 (s, 2H), 8.32 (m, 1H),    7.96 (m, 1H), 7.38 (m, 1H), 7.12 (m, 1H), 6.80 (m, 1H), 4.58 (s,    1H), 4.07 (m, 1H), 3.85 (m, 2H), 3.81 (m, 1H), 3.76 (m, 2H), 3.36    (m, 1H), 3.34 (s, 3H), 3.00 (m, 1H), 2.86 (m, 1H), 2.66 (m, 1H),    2.29 (m, 2H), 2.20 (m, 2H), 2.01 (m, 1H), 1.89 (m, 1H); LCMS (m/z):    446.39 (MH⁺);-   4-(2-(morpholin-4-yl)pyrimidin-5-yl)-N-(3-fluoro-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #43, ¹H NMR (CD₃OD, 300 MHz): δ 9.03 (s, 2H), 8.53 (s, 1H),    8.33 (d, 1H), 7.57 (m, 1H), 7.23 (d, 1H), 7.13 (d, 1H), 6.74 (m,    1H), 4.46 (s, 1H), 3.90 (m, 4H), 3.76 (m, 4H), 3.66 (m, 1H), 3.40    (m, 1H), 3.36 (m, 1H), 3.14 (m, 1H), 2.96 (m, 1H), 2.57 (m, 1H),    2.52 (s, 3H), 2.04 (m, 2H); LCMS (m/z): 463 (MH⁺);-   4-(2-((cyclopropyl)carbonylamino)-pyrimidin-5-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #44, ¹H NMR (CD₃OD, 300 MHz): δ 9.17 (s, 2H), 8.36 (s, 1H),    7.41 (d, 1H), 7.18 (m, 1H), 7.08 (d, 1H), 6.80 (d, 1H), 4.30 (s,    1H), 4.16 (m, 1H), 4.05 (m, 1H), 3.78 (m, 1H), 3.58 (m, 1H), 3.32    (m, 1H), 2.89 (s, 3H), 2.47 (m, 1H), 2.65 (m, 1H), 2.26 (m, 3H),    2.21 (m, 1H), 1.13 (m, 2H), 0.92 (m, 2H); LCMS (m/z): 457 (MH⁺);-   4-(4-(4,5-dihydrothiazol-2-ylcarbamoyl)phenyl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #45, LCMS (m/z): 500 (MH⁺);-   4-(4-(1,1-dimethylethyl)phenyl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #46, ¹H NMR (CD₃OD, 300 MHz): δ 8.34 (m, 2H), 8.04 (m, 2H),    7.56 (m, 1H), 7.53 (m, 2H), 7.20 (m, 1H), 6.97 (m, 1H), 4.25 (d,    2H), 3.80 (m, 1H), 3.5 (m, 2H), 2.97 (m, 3H), 2.30 (m, 6H), 1.36 (m,    9H); LCMS (m/z): 428 (MH⁺);-   4-(4-(morpholin-4-yl)phenyl)-N-(3-fluoro-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine.TFA    salt, compound #47, ¹H NMR (DMSO-d₆): δ 9.54-9.42 (2H, m), 8.39 (1H,    d, J=5.5 Hz), 8.04 (2H, d, J=8.8 Hz), 7.80 (1H, dd, J=16.4, 2.3 Hz),    7.41 (1H, dd, J=8.7, 2.1 Hz), 7.27 (1H, d, J=5.2 Hz), 7.05 (2H, d,    J=9.1 Hz), 6.84 (1H, t, J=9.6 Hz), 4.48 (1H, s), 4.27 (1H, s),    3.79-3.67 (6H, m), 3.34 (1H, d, J=10.7 Hz), 3.26 (4H, app. t, J=4.7    Hz), 3.09 (1H, d, J=11.6 Hz), 2.87 (2H, d, J=5.0 Hz), 2.82 (1H, d,    J=5.0 Hz), 2.35 (1H, d, J=11.0 Hz), 2.11 (1H, d, J=11.0 Hz); MS: 461    (M+H)⁺;-   4-(4-((methyl)aminocarbonylmethyl)-phenyl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine.TFA    salt, compound #48, ¹H NMR (CD₃OD): δ 8.32 (1H, d, J=6.1 Hz), 8.15    (2H, d, J=8.5 Hz), 7.46 (3H, d, J=8.5 Hz), 7.42 (2H, d, J=6.1 Hz),    7.02 (1H, d, J=8.3 Hz), 4.32 (2H, br s), 3.98 (1H, d, J=11.3 Hz),    3.60 (2H, s), 3.52 (2H, d, J=9.4 Hz), 3.18 (1H, d, J=11.6 Hz), 3.00    (3H, s), 2.75 (3H, s), 2.40-2.28 (5H, m); MS: 443 (M+H)-TFA⁺;-   4-(4-((cyclopropyl)aminocarbonyl-methyl)phenyl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #49, ¹H NMR (CD₃OD): δ 8.31 (1H, d, J=6.1 Hz), 8.15 (2H, d,    J=8.5 Hz), 7.47-7.43 (5H, m), 7.03 (1H, d, J=8.3 Hz), 4.33 (2H, d,    J=7.2 Hz), 3.99 (1H, d, J=11.0 Hz), 3.60-3.47 (4H, m), 3.18 (1H, d,    J=11.8 Hz), 3.00 (3H, s), 2.71-2.66 (1H, m), 2.40-2.28 (5H, m),    0.77-0.71 (2H, m), 0.53-0.48 (2H, m); MS: 469 (M+H)⁺;-   4-(6-(methylaminocarbonyl)pyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #50, ¹H NMR (CD₃OD): δ 9.31-9.30 (1H, m), 8.60 (1H, dd,    J=8.3, 2.2 Hz), 8.51-8.44 (2H, m), 8.16 (1H, d, J=8.3 Hz), 7.54 (1H,    dd, J=8.7, 2.6 Hz), 7.49 (1H, d, J=2.2 Hz), 7.33 (1H, d, J=5.0 Hz),    6.96 (1H, d, J=8.5 Hz), 4.26 (2H, d, J=11.6 Hz), 3.77 (1H, d, J=11.3    Hz), 3.54 (1H, d, J=11.3 Hz), 3.45 (1H, dd, J=11.4, 2.6 Hz), 3.26    (1H, dd, J=11.3, 2.2 Hz), 3.00 (3H, s), 2.97 (3H, s), 2.32 (3H, s),    2.30 (2H, d, J=2.8 Hz); MS: 430 (M+H)⁺;-   4-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine.TFA    salt, compound #51x, ¹H NMR (DMSO-d₆): δ 10.75 (1H, s), 9.44 (1H,    s), 8.90 (1H, d, J=1.9 Hz), 8.46 (1H, d, J=5.2 Hz), 8.29 (1H, s),    7.59-7.51 (2H, m), 7.34 (1H, d, J=5.2 Hz), 6.93 (1H, d, J=8.8 Hz),    4.28-4.22 (2H, m), 3.43-3.38 (2H, m), 3.06-2.87 (7H, m), 2.61-2.53    (4H, m), 2.34-2.08 (3H, m), MS: 442 (M+H)-TFA⁺;-   4-(5-((morpholin-4-yl)carbonyl)pyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine.    Bis TFA salt, compound #52, ¹H NMR (CD₃OD): δ 9.36 (1H, d, J=2.2    Hz), 8.74 (1H, d, J=1.9 Hz), 8.59 (1H, dd, J=2.2, 1.9 Hz), 8.49 (1H,    d, J=5.2 Hz), 8.47 (1H, s), 7.53-7.50 (2H, m), 7.37 (1H, d, J=5.2    Hz), 6.97 (1H, d, J=9.4 Hz), 4.27 (2H, d, J=11.0 Hz), 3.80-3.66 (8H,    m), 3.54 (2H, d, J=11.6 Hz), 3.47 (2H, dd, J=11.6, 2.5 Hz), 2.97    (3H, s), 2.33 (3H, s), 2.30 (2H, br s); MS: 486 (M+H)⁺;-   4-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(3-cyano-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #53, ¹H NMR (DMSO-d₆): δ 11.50 (1H, s), 9.69 (1H, s), 8.73    (1H, s), 8.52 (1H, d, J=5.2 Hz), 8.13 (1H, d, J=1.9 Hz), 8.03 (1H,    s), 7.78 (1H, d, J=9.4 Hz), 7.43 (1H, d, J=5.0 Hz), 7.01 (1H, d,    J=9.1 Hz), 4.71 (1H, s), 4.36 (1H, s), 3.98 (1H, d, J=9.1 Hz), 3.72    (2H, d, J=10.7 Hz), 3.12 (1H, d, J=10.7 Hz), 2.86 (2H, d, J=4.4 Hz),    2.80 (1H, br s), 2.41 (1H, d, J=11.8 Hz), 2.18 (1H, d, J=10.7 Hz),    1.47 (6H, s); MS: 483 (M+H)⁺;-   4-(5-methyl-6-(morpholin-4-yl)pyridin-3-yl)-N-(3-fluoro-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #59, LCMS: purity: 99%; MS (m/e): 476 (MH⁺);-   4-(5-methyl-6-(morpholin-4-yl)pyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #60, LCMS: purity: 99%; MS (m/e): 472 (MH⁺);-   5-methyl-4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #67, LCMS: purity: 99%; MS (m/e): 472 (MH⁺);-   5-methyl-4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-fluoro-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #68, LCMS: purity: 99%; MS (m/e): 476 (MH⁺);-   4-(6-(2-(morpholin-4-yl)ethyl)aminopyridin-3-yl)-N-(4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #69, LCMS: purity: 99%; MS (m/e): 487 (MH⁺);-   4-(6-(2-(morpholin-4-yl)ethyl)aminopyridin-3-yl)-N-(3-fluoro-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #70, LCMS: purity: 99%; MS (m/e): 505 (MH⁺);-   4-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(3-methyl-4-((1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #71, ¹H NMR (DMSO-d6): δ 9.81 (s, 1H), 9.23 (s, 1H), 8.95    (m, 1H), 8.52 (s, 1H), 7.88 (m, 3H), 7.24 (d, 1H, J=3.6 Hz), 4.29    (s, 1H), 3.82 (s, 2H), 3.69 (s, 2H), 3.20 (m, 2H), 2.98 (s, 4H),    2.77 (s, 2H), 2.70 (s, 2H), 1.95 (s, 6H); LCMS: purity: 99%; MS    (m/e): 476 (MH⁺);-   4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-methyl-4-((1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #72, ¹H NMR (DMSO-d6): δ 9.29 (s, 1H), 8.92 (d, 1H, J=2.4    Hz), 8.37 (d, 1H, J=5.4 Hz), 8.25 (m, 1H), 7.54 (m, 2H), 7.24 (d,    1H, J=5.4 Hz), 6.95 (d, 1H, J=9.3 Hz), 6.85 (d, 1H J=9.3 Hz), 4.07    (s, 1H), 3.69 (m, 4H), 3.58 (m, 4H), 3.32 (m, 4H), 2.65 (s, 3H),    2.19 (s, 3H), 1.95 (m, 2H); LCMS: purity: 99%; MS (m/e): 458 (MH⁺);-   4-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(3-fluoro-4-((1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #73, LCMS: purity: 99%; MS (m/e): 476 (MH⁺);-   4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-fluoro-4-((1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #74, LCMS: purity: 99%; MS (m/e): 462 (MH⁺);-   4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-methyl-4-(1,5,7-trimethyl-3,7-diazabicyclo[3.3.1]nonan-3-yl)phenyl)pyrimidin-2-amine,    compound #75, ¹H NMR (DMSO-d6): δ 8.92 (d, 1H, J=2.1 Hz), 8.38 (d,    1H, J=5.1 Hz), 8.25 (m, 1H), 7.56 (m, 3H), 7.25 (d, 1H, J=4.8 Hz),    6.95 (d, 1H, J=9.3 Hz), 3.68 (m, 4H), 3.58 (m, 4H), 3.31 (m, 8H),    2.91 (s, 2H), 2.31 (s, 3H), 0.87 (s, 6H); LCMS: purity: 99%; MS    (m/e): 514 (MH⁺);-   4-(6-(dimethylamino)pyridin-3-yl)-N-(3-methyl-4-(1,5,7-trimethyl-3,7-diazabicyclo[3.3.1]nonan-3-yl)phenyl)pyrimidin-2-amine,    compound #76, LCMS: purity: 99%; MS (m/e): 472 (MH⁺);-   4-(6-(cyclohexylamino)pyridin-3-yl)-N-(3-methyl-4-(1,5,7-trimethyl-3,7-diazabicyclo[3.3.1]nonan-3-yl)phenyl)pyrimidin-2-amine,    compound #77, LCMS: purity: 99%; MS (m/e): 526 (MH⁺);-   4-(6-(cyclohexylamino)pyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #78, LCMS: purity: 99%; MS (m/e): 470 (MH⁺);-   4-(6-(cyclohexylamino)pyridin-3-yl)-N-(3-fluoro-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #79, LCMS: purity: 99%; MS (m/e): 474 (MH⁺);-   4-(6-(benzylamino)pyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #80, LCMS: purity: 99%; MS (m/e): 478 (MH⁺);-   4-(6-(benzylamino)pyridin-3-yl)-N-(3-fluoro-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #81, LCMS: purity: 99%; MS (m/e): 482 (MH⁺);-   4-(5-methyl-6-(morpholin-4-yl)pyridin-3-yl)-N-(3-fluoro-4-(1,5,7-trimethyl-3,7-diazabicyclo[3.3.1]nonan-3-yl)phenyl)pyrimidin-2-amine,    compound #82, LCMS: purity: 99%; MS (m/e): 532 (MH⁺);-   4-(6-(dimethylamino)pyridin-3-yl)-N-(3-fluoro-4-(1,5,7-trimethyl-3,7-diazabicyclo[3.3.1]nonan-3-yl)phenyl)pyrimidin-2-amine,    compound #83, LCMS: purity: 99%; MS (m/e): 476 (MH⁺);-   4-(4-(dimethylamino)phenyl)-N-(3-fluoro-4-(1,5,7-trimethyl-3,7-diazabicyclo[3.3.1]nonan-3-yl)phenyl)pyrimidin-2-amine,    compound #84, LCMS: purity: 99%; MS (m/e): 475 (MH⁺);-   4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-fluoro-4-(1,5,7-trimethyl-3,7-diazabicyclo[3.3.1]nonan-3-yl)phenyl)pyrimidin-2-amine,    compound #85, LCMS: purity: 99%; MS (m/e): 518 (MH⁺);-   4-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #86, LCMS: purity: 99%; MS (m/e): 430 (MH⁺);-   4-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(3-fluoro-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #87, LCMS: purity: 99%; MS (m/e): 434 (MH⁺);-   4-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(3-methyl-4-(1,5,7-trimethyl-3,7-diazabicyclo[3.3.1]nonan-3-yl)phenyl)pyrimidin-2-amine,    compound #88, LCMS: purity: 99%; MS (m/e): 486 (MH⁺);-   4-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(3-fluoro-4-(1,5,7-trimethyl-3,7-diazabicyclo[3.3.1]nonan-3-yl)phenyl)pyrimidin-2-amine,    compound #89, LCMS: purity: 99%; MS (m/e): 490 (MH⁺);-   4-(6-(benzyl)pyridin-3-yl)-N-(3-methyl-4-(1,5,7-trimethyl-3,7-diazabicyclo[3.3.1]nonan-3-yl)phenyl)pyrimidin-2-amine,    compound #90, LCMS: purity: 99%; MS (m/e): 534 (MH⁺);-   4-(6-(benzyl)pyridin-3-yl)-N-(3-fluoro-4-(1,5,7-trimethyl-3,7-diazabicyclo[3.3.1]nonan-3-yl)phenyl)pyrimidin-2-amine,    compound #91, LCMS: purity: 99%; MS (m/e): 538 (MH⁺);-   4-(2-(propyl)aminopyrimidin-5-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #92, LCMS: purity: 99%; MS (m/e): 431 (MH⁺);-   4-(2-(propyl)aminopyrimidin-5-yl)-N-(3-fluoro-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #93, LCMS: purity: 99%; MS (m/e): 435 (MH⁺);-   4-(6-(cyclohexylamino)pyridin-3-yl)-N-(3-trifluoromethyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #94, LCMS: purity: 99%; MS (m/e): 524 (MH⁺);-   4-(5-(methyl)sulfonylpyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #95, LCMS: purity: 99%; MS (m/e): 451 (MH⁺);-   4-(6-(dimethylamino)pyridin-3-yl)-N-(3-trifluoromethyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #96, LCMS: purity: 99%; MS (m/e): 470 (MH⁺);-   4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-trifluoromethyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #97, LCMS: purity: 99%; MS (m/e): 512 (MH⁺);-   4-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(3-trifluoromethyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #98, LCMS: purity: 99%; MS (m/e): 484 (MH⁺);-   4-(6-((2-(cyclopropylsulfonyl)aminoethyl)-amino)pyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #99, LCMS: purity: 99%; MS (m/e): 535 (MH⁺);-   4-(6-((2-(cyclopropylsulfonyl)aminoethyl)-amino)pyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-oxa-2-azabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #100, LCMS: purity: 99%; MS (m/e): 522 (MH⁺);-   4-(5-(methyl)sulfonylpyridin-3-yl)-N-(3-fluoro-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #101, LCMS: purity: 99%; MS (m/e): 455 (MH⁺);-   4-(5-(methyl)sulfonylpyridin-3-yl)-N-(3-trifluoromethyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #102, LCMS: purity: 99%; MS (m/e): 505 (MH⁺);-   4-(imidazo[1,2-a]pyridin-6-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #103, ¹H NMR (CD₃OD, 300 MHz): δ 9.29 (s, 1H), 8.42 (m,    1H), 8.06 (m, 1H), 7.96 (s, 1H), 7.64 (m, 2H), 7.55 (m, 1H), 7.49    (m, 1H), 7.27 (m, 1H), 6.99 (m, 1H), 4.29 (m, 2H), 3.79 (m, 1H),    3.52 (m, 3H), 2.99 (s, 3H), 2.32 (m, 5H); MS (ES) 412.0 (M+H);-   4-(4-(5-(4-dimethylaminophenyl)oxazol-2-yl)phenyl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #104, ¹H NMR (CD₃OD, 300 MHz): δ 8.32 (m, 1H), 8.22 (m,    2H), 8.06 (m, 2H), 7.61 (m, 2H), 7.43 (m, 4H), 6.98 (m, 3H), 4.31    (m, 2H), 3.98 (m, 1H), 3.52 (m, 2H), 3.17 (m, 1H), 3.05 (m, 9H),    2.33 (m, 5H); MS (ES) 558.1 (M+H);-   4-(6-methoxy-1H-indol-2-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #105, ¹H NMR (CD₃OD, 300 MHz): δ 7.98 (m, 1H), 7.51 (m,    1H), 7.44 (s, 1H), 7.37 (m, 1H), 7.28 (m, 2H), 7.03 (m, 1H), 6.93    (m, 1H), 6.76 (m, 1H), 4.34 (m, 2H), 3.98 (m, 1H), 3.85 (s, 3H),    3.54 (m, 3H), 2.99 (s, 3H), 2.32 (m, 5H); MS (ES) 441.1 (M+H);-   4-(1-(3-chlorophenyl)-1H-pyrazol-4-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #106, ¹H NMR (CD₃OD, 300 MHz): δ 9.10 (m, 1H), 8.35 (m,    1H), 8.20 (m, 1H), 7.92 (m, 1H), 7.79 (m, 1H), 7.50 (m, 1H), 7.40    (m, 3H), 7.27 (m, 1H), 7.03 (m, 1H), 4.34 (m, 2H), 3.98 (m, 1H),    3.54 (m, 2H), 3.18 (m, 1H), 2.99 (s, 3H), 2.32 (m, 5H); MS (ES)    472.0 (M+H);-   4-(1-methylbenzimidazol-6-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #107, ¹H NMR (CD₃OD, 300 MHz): δ 9.41 (s, 1H), 8.73 (s,    1H), 8.47 (m, 2H), 7.96 (m, 1H), 7.53 (m, 3H), 7.02 (m, 1H), 4.31    (m, 2H), 4.21 (s, 3H), 3.97 (m, 1H), 3.51 (m, 2H), 3.19 (m, 1H),    2.99 (s, 3H), 2.34 (m, 5H); MS (ES) 426.1 (M+H);-   4-(5-cyano-1H-indol-2-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #108, ¹H NMR (CD₃OD, 300 MHz): δ 8.17 (m, 1H), 8.01 (m,    1H), 7.56 (m, 1H), 7.39 (m, 5H), 7.01 (m, 1H), 4.32 (m, 2H), 3.97    (m, 1H), 3.53 (m, 2H), 3.16 (m, 1H), 2.99 (s, 3H), 2.31 (m, 5H); MS    (ES) 436.1 (M+H);-   4-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #109, ¹H NMR (CD₃OD, 300 MHz): δ 8.75 (s, 1H), 8.26 (m,    2H), 7.79 (m, 2H), 7.46 (m, 2H), 7.23 (m, 2H), 7.00 (m, 1H), 6.93    (m, 1H), 4.22 (m, 2H), 3.73 (m, 1H), 3.53 (m, 1H), 3.33 (m, 1H),    3.22 (m, 1H), 2.94 (s, 3H), 2.28 (m, 5H); MS (ES) 456.0 (M+H);-   4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-methyl-4-(7-azabicyclo[2.2.1]heptan-7-yl)phenyl)pyrimidin-2-amine,    compound #110, ¹H NMR (CD₃OD, 300 MHz): δ 8.87 (m, 1H), 8.58 (m,    1H), 8.50 (m, 1H), 7.81 (m, 2H), 7.60 (m, 1H), 7.36 (m, 2H), 4.80    (m, 2H), 3.85 (m, 4H), 3.76 (m, 4H), 2.57 (s, 3H), 2.22 (m, 4H),    1.98 (m, 4H); MS (ES) 443.1 (M+H);-   4-(6-cyanopyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #111, ¹H NMR (CD₃OD, 300 MHz): δ 9.48 (m, 1H), 8.64 (m,    2H), 8.05 (m, 1H), 7.90 (m, 2H), 7.64 (m, 1H), 7.46 (m, 1H), 4.31    (m, 2H), 3.97 (m, 1H), 3.50 (m, 2H), 3.18 (m, 1H), 2.99 (s, 3H),    2.30 (m, 5H); MS (ES) 398.1 (M+H);-   4-(6-cyanopyridin-3-yl)-N-(3-methyl-4-(7-azabicyclo[2.2.1]heptan-7-yl)phenyl)pyrimidin-2-amine,    compound #112, ¹H NMR (CD₃OD, 300 MHz): δ 9.47 (m, 1H), 8.66 (m,    2H), 8.03 (m, 1H), 7.87 (m, 2H), 7.60 (m, 1H), 7.51 (m, 1H), 4.81    (m, 2H), 2.57 (s, 3H), 2.22 (m, 4H), 1.98 (m, 4H); MS (ES) 383.0    (M+H);-   4-(2-oxoindolin-5-yl)-N-(3-methyl-4((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #113, ¹H NMR (CD₃OD, 300 MHz): δ 8.25 (m, 3H), 7.41 (m,    3H), 7.02 (m, 2H), 4.32 (m, 2H), 3.98 (m, 1H), 3.54 (m, 2H), 3.18    (m, 1H), 2.99 (m, 5H), 2.33 (m, 5H); MS (ES) 427.0 (M+H);-   4-(5-cyanopyridin-3-yl)-N-(3-methyl-4((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #114, ¹H NMR (CD₃OD, 300 MHz): δ 8.82 (m, 2H), 7.42 (m,    4H), 6.97 (m, 2H), 4.30 (m, 2H), 3.97 (m, 1H), 3.49 (m, 2H), 3.17    (m, 1H), 2.98 (s, 3H), 2.30 (m, 5H); MS (ES) 398.1 (M+H);-   4-(6-(1H-tetrazol-5-yl)pyridin-3-yl)-N-(3-methyl-4((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #115, ¹H NMR (CD₃OD, 300 MHz): δ 9.49 (m, 1H), 8.72 (m,    1H), 8.51 (m, 1H), 8.36 (m, 1H), 7.53 (m, 2H), 7.40 (m, 1H), 6.98    (m, 1H), 4.29 (m, 2H), 3.96 (m, 1H), 3.49 (m, 2H), 3.16 (m, 1H),    2.65 (s, 3H), 2.32 (m, 5H); MS (ES) 441.1 (M+H);-   4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-cyano-4-((1S,4S)-5-acetyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #116, ¹H NMR (CD₃OD, 300 MHz): δ 8.79 (m, 1H), 8.39 (m,    1H), 8.31 (m, 1H), 7.86 (m, 1H), 7.59 (m, 1H), 7.29 (m, 1H), 7.12    (m, 1H), 6.87 (m, 1H), 4.04 (m, 2H), 3.80 (m, 4H), 3.58 (m, 8H),    2.07 (m, 5H); MS (ES) 497.1 (M+H);-   4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-cyano-4-((1S,4S)-5-methylsulfonyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #117, ¹H NMR (CD₃OD, 300 MHz): δ 8.83 (m, 1H), 8.41 (m,    1H), 8.32 (m, 1H), 7.88 (m, 1H), 7.60 (m, 1H), 7.34 (m, 1H), 7.17    (m, 1H), 6.93 (m, 1H), 4.55 (m, 2H), 4.04 (m, 3H), 3.82 (m, 5H),    3.73 (m, 4H), 2.96 (s, 3H), 2.01 (m, 2H); MS (ES) 533.1 (M+H);-   4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-cyano-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #118, ¹H NMR (CD₃OD, 300 MHz): δ 8.83 (m, 1H), 8.49 (m,    1H), 8.39 (m, 1H), 8.00 (m, 1H), 7.74 (m, 1H), 7.33 (m, 1H), 7.22    (m, 1H), 6.98 (m, 1H), 4.83 (m, 1H), 4.41 (m, 1H), 4.05 (m, 3H),    3.85 (m, 4H), 3.74 (m, 4H), 3.65 (m, 1H), 3.00 (s, 3H), 2.39 (m,    2H); MS (ES) 469.1 (M+H);-   4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-cyano-4-((1S,4S)-5-cyclopentyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #119, ¹H NMR (CD₃OD, 300 MHz): δ 8.83 (m, 1H), 8.49 (m,    1H), 8.40 (m, 1H), 8.01 (m, 1H), 7.75 (m, 1H), 7.34 (m, 1H), 7.23    (m, 1H), 6.99 (m, 1H), 4.57 (m, 1H), 4.08 (m, 1H), 3.81 (m, 11H),    3.46 (m, 1H), 2.33 (m, 2H), 1.76 (m, 8H); MS (ES) 523.1 (M+H);-   4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-methyl-4-(1,4-diazabicyclo[3.2.1]octan-4-yl)phenyl)pyrimidin-2-amine,    compound #120, ¹H NMR (CD₃OD, 300 MHz): δ 8.93 (m, 1H), 8.40 (m,    1H), 8.29 (m, 1H), 7.74 (m, 1H), 7.52 (m, 2H), 7.29 (m, 1H), 7.19    (m, 1H), 7.05 (m, 1H), 3.97 (m, 1H), 3.82 (m, 4H), 3.69 (m, 9H),    3.37 (m, 1H), 3.14 (m, 2H), 2.37 (s, 3H), 2.16 (m, 2H); MS (ES)    458.1 (M+H);-   4-(2-oxoindolin-5-yl)-N-(3-methyl-4-(1,4-diazabicyclo[3.2.1]octan-4-yl)phenyl)pyrimidin-2-amine,    compound #121, ¹H NMR (CD₃OD, 300 MHz): δ 8.20 (m, 3H), 7.44 (m,    3H), 7.12 (m, 2H), 3.95 (m, 1H), 3.60 (m, 5H), 3.36 (m, 1H), 3.10    (m, 4H), 2.37 (s, 3H), 2.16 (m, 2H); MS (ES) 427.0 (M+H);-   (1-methylbenzimidazol-6-yl)-N-(3-methyl-4-(1,4-diazabicyclo[3.2.1]octan-4-yl)phenyl)pyrimidin-2-amine,    compound #122, ¹H NMR (CD₃OD, 300 MHz): δ 8.40 (m, 2H), 8.24 (m,    1H), 8.14 (m, 1H), 7.76 (m, 1H), 7.67 (m, 1H), 7.60 (m, 1H), 7.39    (m, 1H), 7.14 (m, 1H), 3.99 (s, 3H), 3.94 (m, 1H), 3.60 (m, 5H),    3.36 (m, 1H), 3.14 (m, 2H), 2.38 (s, 3H), 2.16 (m, 2H); MS (ES)    426.1 (M+H);-   4-(imidazo[1,2-a]pyridin-6-yl)-N-(3-methyl-4-(1,4-diazabicyclo[3.2.1]octan-4-yl)phenyl)pyrimidin-2-amine,    compound #123, ¹H NMR (CD₃OD, 300 MHz): δ 9.30 (m, 1H), 8.45 (m,    1H), 8.39 (m, 1H), 8.07 (m, 1H), 7.96 (m, 1H), 7.60 (m, 3H), 7.30    (m, 1H), 7.15 (m, 1H), 3.95 (m, 1H), 3.60 (m, 5H), 3.36 (m, 1H),    3.14 (m, 2H), 2.37 (s, 3H), 2.16 (m, 2H); MS (ES) 412.1 (M+H);-   4-(2H-benzo[b][1,4]oxazin-3(4H)-on-6-yl)-N-(3-fluoro-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #124, ¹H NMR (CD₃OD, 300 MHz): δ 8.36 (m, 1H), 7.75 (m,    3H), 7.33-6.77 (m, 4H), 4.63 (s, 2H), 4.59 (s, 1H), 4.31 (s, 1H),    3.92 (m, 2H), 3.41 (m, 1H), 3.15 (m, 1H), 2.97 (s, 3H), 2.33 (m,    2H); MS (ES) 447.09 (M+H);-   4-(2,2,4-trimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #125, ¹H NMR (CD₃OD, 300 MHz) 8.80 (m, 1H), 8.39 (m, 1H),    8.01 (m, 2H), 7.55 (m, 2H), 7.26 (m, 1H), 6.98 (m, 1H), 4.63 (s,    1H), 4.31 (s, 1H), 4.25 (s, 1H), 3.50 (m, 4H), 3.28 (m, 2H), 2.99    (s, 3H), 2.32 (m, 5H), 1.54 (m, 6H); MS (ES) 486.21 (M+H);-   4-(2,2,4-trimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(3-fluoro-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #126, ¹H NMR (CD₃OD, 300 MHz): δ 8.75 (m, 1H), 8.39 (m,    2H), 7.96 (m, 1H), 7.65 (m, 1H), 7.25 (m, 2H), 6.79 (m, 1H), 4.57    (s, 1H), 4.29 (s, 1H), 3.84 (m, 2H), 3.48 (m, 5H), 3.30 (m, 6H),    2.94 (m, 3H), 2.30 (m, 2H); MS (ES) 490.19 (M+H);-   4-(5-(3-methylpiperidin-1-yl)pyrazin-2-yl)-N-(3-fluoro-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #127, ¹H NMR (CD₃OD, 300 MHz): δ 9.00 (m, 1H), 8.31 (m,    2H), 7.57 (m, 2H), 7.31 (m, 1H), 6.85 (m, 1H), 4.64 (s, 1H), 4.45    (m, 2H), 4.33 (s, 1H), 4.29 (s, 1H), 3.96 (m, 2H), 3.45 (m, 1H),    3.19 (m, 1H), 3.07 (m, 1H), 2.98 (s, 3H), 2.74 (m, 2H), 2.35 (m,    2H), 1.19-1.26 (m, 4H), 1.00 (d, J=5.4 Hz, 3H); MS (ES) 475.48    (M+H);-   4-(4-(t-butylcarbonylamino)phenyl)-N-(3-fluoro-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #128, ¹H NMR (CD₃OD, 300 MHz): δ 8.42 (m, 2H), 8.10 (m,    2H), 7.75 (m, 3H), 7.25 (m, 2H), 4.57 (s, 1H), 4.26 (s, 1H), 3.81    (m, 2H), 3.46 (m, 2H), 2.93 (s, 3H), 2.29 (m, 2H), 1.34 (s, 9H); MS    (ES) 475.12 (M+H);-   4-(4-(t-butylcarbonylamino)phenyl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #129, ¹H NMR (CD₃OD, 300 MHz): δ 8.34 (m, 2H), 8.10 (m,    2H), 7.72 (m, 2H), 7.51 (m, 2H), 7.22 (m, 1H), 6.95 (m, 1H), 4.29    (s, 1H), 4.22 (s, 1H), 3.76 (m, 2H), 3.47 (m, 2H), 2.97 (m, 3H),    2.31 (m, 5H), 1.32 (s, 9H); MS (ES) 471.15 (M+H);-   4-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #130, ¹H NMR (CD₃OD, 300 MHz): δ 8.68 (m, 1H), 8.48 (m,    1H), 8.39 (m, 1H), 7.49 (m, 2H), 7.27 (m, 1H), 6.96 (m, 1H), 4.23    (m, 2H), 3.72 (m, 1H), 3.50 (m, 2H), 3.26 (m, 1H), 2.95 (s, 3H),    2.66 (m, 1H), 2.32 (s, 3H), 2.30 (m, 2H), 1.54 (s, 6H); MS (ES)    472.22 (M+H);-   4-(6-(acetamido)pyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #132, ¹H NMR (CD₃OD, 300 MHz): δ 9.02 (m, 1H), 8.42 (m,    2H), 8.21 (m, 2H), 7.52 (m, 2H), 7.23 (m, 1H), 6.97 (m, 1H), 4.29    (s, 1H), 4.30 (s, 1H), 4.24 (s, 1H), 3.77 (m, 1H), 3.52 (m, 2H),    2.97 (s, 3H), 2.31 (m, 5H), 2.21 (s, 3H); MS (ES) 430.07 (M+H);-   4-(4-((pyridin-2-yl)aminocarbonyl)phenyl)-N-(3-fluoro-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #133, ¹H NMR (CD₃OD, 300 MHz): δ 8.50-8.15 (m, 6H), 8.00    (m, 1H), 7.73 (m, 1H), 7.39 (m, 4H), 6.83 (m, 1H), 4.61 (s, 1H),    4.32 (s, 1H), 3.92 (m, 3H), 3.44 (m, 1H), 3.18 (m, 1H), 2.97 (s,    3H), 2.37 (m, 2H); MS (ES) 496.05 (M+H);-   4-(4-((pyridin-2-yl)aminocarbonyl)phenyl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #134, ¹H NMR (CD₃OD, 300 MHz): δ 8.45-7.96 (m, 8H), 7.50    (m, 4H), 6.99 (m, 1H), 4.61 (s, 1H), 4.30 (m, 2H), 3.98 (m, 1H),    3.50 (m, 2H), 3.15 (m, 1H), 2.99 (s, 3H), 2.33 (m, 5H); MS (ES)    492.08 (M+H);-   4-(4-(methylsulfonylamino)phenyl)-N-(3-fluoro-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #135, ¹H NMR (CD₃OD, 300 MHz): δ 8.36 (m, 1H), 8.13 (m,    2H), 7.65 (m, 2H), 7.32 (m, 3H), 6.83 (m, 1H), 4.62 (s, 1H), 4.32    (s, 1H), 3.92 (m, 2H), 3.39 (m, 1H), 3.20 (m, 1H), 3.05 (s, 3H),    2.97 (s, 3H), 2.34 (m, 2H); MS (ES) 469.03 (M+H);-   4-(4-(methylsulfonylamino)phenyl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #136, ¹H NMR (CD₃OD, 300 MHz): δ 8.21 (m, 3H), 7.39 (m,    5H), 7.01 (m, 1H), 4.34 (m, 2H), 3.99 (m, 1H), 3.77 (m, 1H), 3.53    (m, 2H), 3.20 (m, 1H), 3.07 (s, 3H), 2.99 (s, 3H), 2.66 (m, 1H),    2.33 (m, 5H); MS (ES) 465.05 (M+H);-   4-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #137, ¹H NMR (CD₃OD, 300 MHz): δ 8.67 (m, 1H), 8.48 (m,    1H), 8.39 (m, 2H), 7.98 (m, 1H), 7.54 (m, 2H), 7.20 (m, 1H), 6.69    (m, 2H), 4.63 (s, 1H), 4.33 (s, 1H), 3.72 (m, 2H), 3.37 (m, 1H),    3.24 (m, 1H), 2.93 (s, 3H), 2.34 (s, 2H), 1.54 (s, 6H); MS (ES)    458.21 (M+H);-   4-(4-(3-cyclopropylureido)phenyl)-N-(4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #139, ¹H NMR (CD₃OD, 300 MHz): δ 8.28 (m, 1H), 8.18 (m,    1H), 8.03 (m, 2H), 7.55 (m, 3H), 7.13 (m, 2H), 6.69 (m, 2H), 4.64    (s, 1H), 4.35 (s, 1H), 3.77 (m, 2H), 3.36 (m, 2H), 2.95 (s, 3H),    2.61 (m, 1H), 2.35 (m, 3H), 0.76 (m, 1H), 0.53 (m, 3H); MS (ES)    456.52 (M+H);-   4-(6-(2-(morpholin-4-yl)acetamido)pyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #141, ¹H NMR (CD₃OD, 300 MHz): δ 9.10 (m, 1H), 8.51 (m,    2H), 8.39 (m, 1H), 7.49 (m, 2H), 7.31 (m, 1H), 6.99 (m, 1H), 4.28    (m, 4H), 3.97 (m, 6H), 3.48 (m, 4H), 3.34 (m, 1H), 3.21 (m, 1H),    2.99 (s, 3H), 2.32 (m, 6H); MS (ES) 515.72 (M+H);-   4-(6-(2-(morpholin-4-yl)acetamido)pyridin-3-yl)-N-(4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #142, ¹H NMR (CD₃OD, 300 MHz): δ 9.10 (m, 1H), 8.51 (m,    1H), 8.36 (m, 2H), 7.52 (m, 2H), 7.32 (m, 1H), 6.73 (m, 1H), 4.66    (s, 1H), 4.36 (s, 1H), 4.26 (s, 1H), 4.12-3.78 (m, 6H), 3.46 (m,    4H), 3.21 (m, 2H), 2.97 (s, 3H), 2.33 (m, 3H); MS (ES) 501.06 (M+H);-   4-(6-(2-(morpholin-4-yl)acetamido)pyridin-3-yl)-N-(3-fluoro-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #143, ¹H NMR (CD₃OD, 300 MHz): δ 9.05 (m, 1H), 8.51 (m,    1H), 8.24 (m, 2H), 7.66 (m, 1H), 7.29 (m, 2H), 6.80 (m, 1H), 4.66    (s, 1H), 4.59 (m, 1H), 4.31 (s, 1H), 3.80 (m, 6H), 3.50 (m, 1H),    3.26 (m, 2H), 2.96 (s, 3H), 2.64 (m, 4H), 2.32 (m, 3H); MS (ES)    519.06 (M+H);-   4-(6-(acetamido)pyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-oxa-2-azabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #147, ¹H NMR (CD₃OD, 300 MHz): δ 9.03 (m, 1H), 8.42 (m,    2H), 8.22 (m, 2H), 7.41 (m, 1H), 7.20 (m, 1H), 6.88 (m, 1H), 4.58    (s, 1H), 4.17 (s, 1H), 4.05 (m, 1H), 3.82 (m, 1H), 3.23 (m, 2H),    2.28 (m, 3H), 2.21 (s, 3H), 2.03 (m, 1H), 1.91 (m, 1H); MS (ES)    416.97 (M+H);-   4-(6-aminopyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-ethylcarbonyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #148, ¹H NMR (CD₃OD, 300 MHz): δ 8.65 (m, 1H), 8.38 (m,    2H), 8.06 (m, 1H), 7.40 (m, 2H), 7.14 (m, 1H), 6.89 (m, 1H), 4.65    (s, 1H), 4.23 (s, 1H), 4.19 (m, 1H), 3.70-3.36 (m, 3H), 2.65 (s,    3H), 2.44 (m, 2H), 2.37 (s, 3H), 2.14-1.89 (m, 2H), 1.14 (m, 2H); MS    (ES) 430.02 (M+H);-   4-(6-(acetamido)pyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-ethylcarbonyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #149, ¹H NMR (CD₃OD, 300 MHz): δ 9.03 (m, 1H), 8.39 (m,    2H), 8.22 (m, 2H), 7.42 (m, 2H), 7.21 (m, 1H), 6.91 (m, 1H), 4.65    (s, 1H), 4.25 (s, 1H), 3.68-3.32 (m, 5H), 2.66-2.32 (m, 2H), 2.29    (s, 3H), 2.21 (s, 3H), 2.08-1.82 (m, 2H), 1.14 (m, 2H); MS (ES)    472.06 (M+H);-   4-(6-aminopyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-methylsulfonyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #150, ¹H NMR (CD₃OD, 300 MHz): δ 8.68 (m, 1H), 8.28 (m,    2H), 8.09 (m, 1H), 7.41 (m, 2H), 7.09 (m, 1H), 6.75 (m, 1H), 4.65    (s, 1H), 4.20 (m, 1H), 4.19 (m, 1H), 3.71-3.39 (m, 3H), 2.66-2.39    (m, 2H), 2.29 (s, 3H), 2.21 (s, 3H), 2.13-1.88 (m, 2H), 1.14 (m,    2H); MS (ES) 451.99 (M+H);-   4-(6-(methylsulfonylamino)pyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #151, ¹H NMR (CD₃OD, 300 MHz): δ 8.96 (m, 1H), 8.43 (m,    1H), 8.30 (m, 1H), 7.54 (m, 2H), 7.23 (m, 1H), 7.15 (m, 1H), 6.97    (m, 1H), 4.30 (s, 1H), 4.25 (s, 1H), 3.80-3.37 (m, 3H), 3.23 (m,    2H), 2.98 (s, 3H), 2.66 (m, 2H), 2.32 (brs, 6H); MS (ES) 466.03    (M+H);-   4-(6-(2-(dimethylamino)acetamido)-pyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #152, ¹H NMR (CD₃OD, 300 MHz): δ 8.52 (m, 1H), 8.31 (m,    1H), 8.20 (m, 1H), 7.52 (m, 2H), 7.21 (m, 2H), 6.96 (m, 1H), 4.31    (s, 1H), 4.24 (s, 1H), 3.91-3.48 (m, 5H), 2.99 (s, 3H), 2.83 (s,    3H), 2.65 (s, 3H), 2.32 (m, 6H); MS (ES) 473.04 (M+H);-   4-(6-(methylsulfonylamino)pyridin-3-yl)-N-(3-fluoro-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #153, ¹H NMR (CD₃OD, 300 MHz): δ 8.94 (m, 1H), 8.39 (m,    3H), 7.62 (m, 1H), 7.22 (m, 3H), 6.78 (m, 1H), 4.56 (s, 1H), 4.29    (s, 1H), 3.79-3.43 (m, 5H), 2.93 (m, 2H), 2.66 (m, 1H), 2.30 (m,    3H); MS (ES) 469.99 (M+H);-   4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(4-(8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)pyrimidin-2-amine,    compound #155, ¹H NMR (CD₃OD, 300 MHz): δ 8.90 (m, 1H), 8.49 (m,    1H), 8.25 (m, 2H), 7.59 (m, 2H), 7.13 (m, 1H), 6.94 (m, 1H), 6.87    (m, 1H), 3.93 (m, 2H), 3.78 (m, 4H), 3.61 (m, 6H), 3.13 (m, 2H),    2.81 (s, 3H), 2.19 (m, 4H); MS (ES) 458.03 (M+H);-   4-(6-(methylsulfonylamino)pyridin-3-yl)-N-(4-(8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)pyrimidin-2-amine,    compound #156, ¹H NMR (CD₃OD, 300 MHz): δ 8.90 (m, 1H), 8.36 (m,    3H), 7.75 (m, 1H), 7.56 (m, 2H), 7.13 (m, 2H), 6.91 (m, 2H), 3.97    (m, 2H), 3.72 (m, 2H), 3.19 (m, 2H), 2.83 (s, 3H), 2.25 (m, 5H); MS    (ES) 466.03 (M+H);-   4-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(4-(8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)pyrimidin-2-amine,    compound #157, ¹H NMR (CD₃OD, 300 MHz): δ 8.67 (m, 1H), 8.38 (m,    1H), 7.99 (m, 1H), 7.59 (m, 2H), 7.21 (m, 1H), 6.95 (m, 2H), 3.97    (m, 2H), 3.68 (m, 2H), 3.17 (m, 3H), 2.85 (s, 3H), 2.65 (m, 1H),    2.22 (m, 4H), 1.55 (s, 6H); MS (ES) 472.09 (M+H);-   4-(6-aminopyridin-3-yl)-N-(4-(8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)pyrimidin-2-amine,    compound #158, ¹H NMR (CD₃OD, 300 MHz): δ 8.87 (m, 1H), 8.28 (m,    2H), 8.15 (m, 1H), 7.58 (m, 2H), 7.09 (m, 1H), 6.93 (m, 2H), 6.65    (m, 1H), 4.03 (m, 2H), 3.68 (m, 2H), 3.25 (m, 3H), 2.89 (s, 3H),    2.64 (m, 1H), 2.23 (m, 4H); MS (ES) 388.04 (M+H);-   4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-methyl-4-(1,4-diazabicyclo[3.2.2]nonan-4-yl)phenyl)pyrimidin-2-amine,    compound #159, ¹H NMR (CD₃OD, 300 MHz): δ 8.27 (m, 3H), 7.51 (m,    2H), 7.15 (m, 2H), 6.86 (m, 1H), 3.80 (m, 4H), 3.60 (m, 7H), 3.46    (m, 4H), 3.30 (m, 2H), 2.41 (m, 2H), 2.35 (s, 3H), 2.07 (m, 2H); MS    (ES) 472.12 (M+H);-   4-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(3-methyl-4-(1,4-diazabicyclo[3.2.2]nonan-4-yl)phenyl)pyrimidin-2-amine,    compound #160, ¹H NMR (CD₃OD, 300 MHz): δ 8.64 (m, 1H), 8.47 (m,    1H), 8.38 (m, 1H), 7.95 (m, 1H), 7.51 (m, 2H), 7.14 (m, 2H),    3.51-3.43 (m, 9H), 2.40 (m, 2H), 2.34 (s, 3H), 2.34 (m, 2H), 1.54    (s, 6H); MS (ES) 486.11 (M+H);-   4-(4-((pyridin-2-yl)aminocarbonyl)phenyl)-N-(3-methyl-4-(1,4-diazabicyclo[3.2.2]nonan-4-yl)phenyl)pyrimidin-2-amine,    compound #161, ¹H NMR (CD₃OD, 300 MHz): δ 8.47-8.22 (m, 4H), 8.10    (m, 3H), 7.84 (m, 1H), 7.60 (m, 2H), 7.35-7.15 (m, 3H), 3.61-3.48    (m, 9H), 2.44 (m, 2H), 2.37 (s, 3H), 2.12 (m, 2H); MS (ES) 506.06    (M+H);-   4-(4-(acetamido)phenyl)-N-(4-(8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)pyrimidin-2-amine,    compound #162, ¹H NMR (CD₃OD, 300 MHz): δ 8.34 (m, 1H), 8.10 (m,    2H), 7.66 (m, 4H), 7.19 (m, 1H), 6.95 (m, 2H), 3.99 (m, 2H), 3.68    (m, 2H), 3.13 (m, 2H), 2.86 (s, 3H), 2.23 (m, 4H), 2.16 (s, 3H); MS    (ES) 429.32 (M+H);-   4-(2-(diethylamino)thiazol-4-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #163, ¹H NMR (CD₃OD, 300 MHz): δ 8.37 (m, 1H), 7.53 (m,    1H), 7.46 (m, 2H), 7.29 (m, 1H), 6.95 (m, 1H), 4.31 (s, 1H), 4.23    (s, 1H), 3.56 (m, 6H), 2.99 (s, 3H), 2.31 (brs, 5H), 1.27 (m, 8H);    MS (ES) 450.30 (M+H);-   4-(2-(diethylamino)thiazol-4-yl)-N-(3-fluoro-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #164, ¹H NMR (CD₃OD, 300 MHz): δ 8.47 (m, 1H), 8.38 (m,    1H), 7.70 (m, 1H), 7.45 (m, 1H), 7.29 (m, 2H), 6.77 (m, 1H), 4.54    (s, 1H), 4.23 (s, 1H), 3.60 (m, 5H), 3.03 (m, 1H), 2.91 (s, 3H),    2.29 (m, 2H), 1.27 (m, 8H); MS (ES) 454.00 (M+H);-   4-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(3-methyl-4-(8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)pyrimidin-2-amine,    compound #165, ¹H NMR (CD₃OD, 300 MHz): δ 8.70 (m, 1H), 8.42 (m,    1H), 8.01 (m, 1H), 7.56 (m, 2H), 7.27 (m, 3H), 4.01 (brs, 2H),    3.25-3.10 (m, 3H), 2.89 (s, 3H), 2.41 (s, 3H), 2.31 (m, 5H), 1.55    (s, 6H); MS (ES) 486.08 (M+H);-   4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-methyl-4-(8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)pyrimidin-2-amine,    compound #166, ¹H NMR (CD₃OD, 300 MHz): δ 8.88 (m, 1H), 8.42 (m,    1H), 8.31 (m, 1H), 7.48 (m, 2H), 7.35 (m, 1H), 7.21 (m, 2H), 4.03    (brs, 2H), 3.85-3.74 (m, 7H), 3.34 (m, 1H), 3.12 (m, 2H), 2.89 (s,    3H), 2.67 (s, 3H), 2.40 (m, 6H); MS (ES) 472.13 (M+H);-   4-(6-(methylsulfonylamino)pyridin-3-yl)-N-(3-methyl-4-(8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)pyrimidin-2-amine,    compound #167, ¹H NMR (CD₃OD, 300 MHz): δ 8.39 (m, 1H), 8.15 (m,    2H), 7.56 (m, 2H), 7.34 (m, 2H), 7.26 (m, 2H), 7.16 (m, 2H), 4.01    (brs, 2H), 3.44-3.10 (m, 3H), 3.24 (m, 1H), 3.05 (s, 3H), 2.89 (s,    3H), 2.28 (m, 6H); MS (ES) 479.08 (M+H);-   4-(4-(t-butylcarbonylamino)phenyl)-N-(3-methyl-4-(8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)pyrimidin-2-amine,    compound #168, ¹H NMR (CD₃OD, 300 MHz): δ 8.33 (m, 1H), 8.15 (m,    2H), 7.78 (m, 2H), 7.54 (m, 2H), 7.41 (m, 1H), 7.20 (m, 1H), 4.02    (brs, 2H), 3.30-3.08 (m, 3H), 3.08 (s, 3H), 2.66 (s, 3H), 2.40 (m,    5H), 1.32 (s, 9H); MS (ES) 485.62 (M+H);-   4-(1H-pyrrol-3-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #169, ¹H NMR (CD₃OD, 300 MHz): δ 8.27 (m, 1H), 8.17 (m,    1H), 7.51 (m, 3H), 6.94 (m, 2H), 4.30 (s, 1H), 4.22 (s, 1H), 3.76    (m, 1H), 3.46 (m, 2H), 3.29 (s, 3H), 2.97 (s, 3H), 2.31 (m, 4H); MS    (ES) 361.07 (M+H);-   4-(1H-pyrrol-3-yl)-N-(4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #170, e¹H NMR (CD₃OD, 300 MHz): δ 8.10 (m, 1H), 7.52 (m,    3H), 6.93 (m, 2H), 6.80 (m, 1H), 6.70 (m, 2H), 4.63 (s, 1H), 4.35    (s, 1H), 3.75 (m, 2H), 3.34 (m, 2H), 2.95 (s, 3H), 2.34 (m, 2H); MS    (ES) 347.04 (M+H);-   4-(1H-pyrrol-3-yl)-N-(3-trifluoromethyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #171, ¹H NMR (CD₃OD, 300 MHz): δ 8.41 (m, 2H), 8.23 (m,    1H), 7.82 (m, 1H), 7.55 (s, 1H), 7.38 (m, 1H), 6.99 (m, 1H), 6.81    (m, 1H), 6.73 (m, 1H), 4.33 (s, 1H), 4.03 (s, 1H), 3.70 (m, 3H),    3.24 (m, 2H), 2.97 (s, 3H), 2.34 (m, 2H); MS (ES) 415.04 (M+H);-   4-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(3-trifluoromethyl-4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #172, ¹H NMR (CD₃OD, 300 MHz): δ 8.69 (m, 1H), 8.48 (m,    2H), 8.31 (m, 1H), 8.03 (m, 1H), 7.86 (m, 1H), 7.33 (m, 2H), 4.33    (s, 1H), 4.08 (s, 1H), 3.65-3.55 (m, 3H), 3.22 (m, 1H), 2.97 (s,    3H), 2.34 (m, 2H), 1.55 (s, 6H); MS (ES) 526.11 (M+H);-   4-(6-ethoxypyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #173, ¹H NMR (DMSO-d₆): δ 9.30 (s, 1H), 8.92 (s, 1H), 8.42    (d, 1H, J=4.3 Hz), 8.37 (dd, 1H, J=2.3 and 8.8 Hz), 7.47 (d, 1H,    J=8.8 Hz), 7.42 (s, 1H), 7.28 (d, 1H, J=4.9 Hz), 6.93 (d, 1H, J=8.5    Hz), 6.74 (d, 1H, J=8.5 Hz), 4.36 (qt, 2H, J=7.0 Hz), 3.88 (s, 1H),    3.17 (app qt, 2H, J=9.1 Hz), 2.73 (d, 1H, J=9.0 Hz), 2.66 (d, 1H,    J=9.0 Hz), 2.25 (s, 3H), 2.18 (s, 3H), 1.77 (d, 1H, J=9.0 Hz), 1.68    (d, 1H, J=9.0 Hz), 1.32 (t, 3H, J=7.0 Hz); LCMS: purity: 99%; MS    (m/e): 417 (MH⁺);-   4-(6-ethoxypyridin-3-yl)-N-(3-fluoro-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #174, LCMS: purity: 99%; MS (m/e): 421 (MH⁺);-   4-(2-(dimethylamino)thiazol-4-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #175, ¹H NMR (DMSO-d₆): δ 9.24 (s, 1H), 8.43 (d, 1H, J=4.9    Hz), 7.53 (d, 1H, J=16.7 Hz), 7.51 (m, 1H), 7.44 (s, 1H), 7.19 (d,    1H, J=4.9 Hz), 6.76 (d, 1H, J=8.5 Hz), 3.90 (s, 1H), 3.42 (s, 1H),    3.19 (app qt, 2H, J=9.1 Hz), 3.08 (s, 6H), 2.78 (s, 2H), 2.34 (s,    3H), 2.18 (s, 3H), 1.83 (d, 1H, J=9.0 Hz), 1.73 (d, 1H, J=9.0 Hz);    LCMS: purity: 99%; MS (m/e): 422 (MH⁺);-   4-(2-(dimethylamino)thiazol-4-yl)-N-(3-fluoro-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #176, ¹H NMR (DMSO-d₆): δ 9.43 (s, 1H), 8.45 (d, 1H, J=4.9    Hz), 7.53 (d, 1H, J=16.7 Hz), 7.51 (m, 1H), 7.38 (d, 1H, J=7.3 Hz),    7.21 (d, 1H, J=4.9 Hz), 6.68 (t, 1H, J=9.1 Hz), 4.14 (s, 1H), 3.39    (d, 1H, J=9.3 Hz), 3.16 (d, 1H, J=9.3 Hz), 3.08 (s, 6H), 2.72 (d,    1H, J=9.0 Hz), 2.59 (d, 1H, J=9.0 Hz), 2.23 (s, 3H), 1.79 (d, 1H,    J=9.0 Hz), 1.69 (d, 1H, J=9.0 Hz); LCMS: purity: 99%; MS (m/e): 426    (MH⁺);-   4-(5-(morpholin-4-yl)pyrazin-2-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #178, ¹H NMR (DMSO-d₆): δ 9.27 (s, 1H), 8.98 (s, 1H), 8.43    (d, 1H, J=4.9 Hz), 8.40 (s, 1H), 7.49 (d, 1H, J=8.8 Hz), 7.42 (s,    1H), 7.36 (d, 1H, J=4.9 Hz), 6.75 (d, 1H, J=8.8 Hz), 3.88 (s, 1H),    3.69-3.67 (m, 8H), 3.17 (app qt, 2H, J=9.1 Hz), 2.73 (d, 1H, J=9.1    Hz), 2.66 (d, 1H, J=9.1 Hz), 2.25 (s, 3H), 2.19 (s, 3H), 1.76 (d,    1H, J=8.8 Hz), 1.69 (d, 1H, J=8.8 Hz); LCMS: purity: 90%; MS (m/e):    459 (MH⁺);-   4-(5-(morpholin-4-yl)pyrazin-2-yl)-N-(3-fluoro-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #179, ¹H NMR (DMSO-d₆): δ 9.48 (s, 1H), 8.98 (s, 1H), 8.47    (d, 1H, J=4.9 Hz), 8.42 (s, 1H), 7.64 (d, 1H, J=16.7 Hz), 7.40-7.34    (m, 2H), 6.71 (d, 1H, J=9.1 Hz), 4.16 (s, 1H), 3.69-3.68 (m, 8H),    3.39 (d, 1H, J=9.6 Hz), 3.17 (d, 1H, J=9.6 Hz), 2.72 (d, 1H, J=9.1    Hz), 2.59 (d, 1H, J=9.1 Hz), 2.22 (s, 3H), 1.79 (d, 1H, J=8.8 Hz),    1.69 (d, 1H, J=8.8 Hz); LCMS: purity: 99%; MS (m/e): 463 (MH⁺);-   4-(4-(1-ethoxyethyl)phenyl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #181, LCMS: purity: 99%; MS (m/e): 444 (MH⁺);-   4-(4-(1-ethoxyethyl)phenyl)-N-(3-fluoro-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #182, LCMS: purity: 99%; MS (m/e): 447 (MH⁺);-   4-(6-(dimethylamino)pyridin-3-yl)-N-(4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #183, ¹H NMR (DMSO-d₆): δ 9.09 (s, 1H), 8.87 (s, 1H), 8.29    (d, 1H, J=4.9 Hz), 8.19 (d, 1H, J=8.8 Hz), 7.53 (d, 2H, J=8.5 Hz),    7.14 (d, 1H, J=5.3 Hz), 6.73 (d, 1H, J=9.1 Hz), 6.53 (d, 2H, J=8.5    Hz), 4.21 (s, 1H), 3.35 (s, 1H), 3.26 (s, 1H), 3.09-3.04 (m, 7H),    2.73 (d, 1H, J=9.6 Hz), 2.21 (s, 3H), 1.82 (d, 1H, J=8.8 Hz), 1.73    (d, 1H, J=8.8 Hz); LCMS: purity: 99%; MS (m/e): 402 (MH⁺);-   4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #184, ¹H NMR (DMSO-d₆): δ 9.13 (s, 1H), 8.90 (d, 1H, J=2.0    Hz), 8.33 (d, 1H, J=4.7 Hz), 8.24 (dd, 1H, J=2.0 and 8.8 Hz), 7.52    (d, 2H, J=8.8 Hz), 7.18 (d, 1H, J=4.7 Hz), 6.94 (d, 1H, J=8.8 Hz),    6.53 (d, 2H, J=8.8 Hz), 4.20 (s, 1H), 3.69-3.67 (m, 4H), 3.56 (br s,    4H), 3.35 (s, 1H), 3.27 (s, 1H), 3.09 (d, 1H, J=8.8 Hz), 2.73 (d,    1H, J=8.8 Hz), 2.21 (s, 3H), 1.82 (d, 1H, J=8.8 Hz), 1.73 (d, 1H,    J=8.8 Hz); LCMS: purity: 99%; MS (m/e): 444 (MH⁺);-   4-(4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #185, ¹H NMR (DMSO-d₆): δ 9.08 (s, 1H), 8.49 (d, 1H, J=1.8    Hz), 8.28 (d, 1H, J=4.9 Hz), 7.58 (d, 1H, J=1.8 Hz), 7.49 (d, 2H,    J=8.8 Hz), 7.14 (d, 1H, J=4.9 Hz), 6.53 (d, 2H, J=8.8 Hz), 4.21 (s,    3H), 3.51-3.50 (m, 2H), 3.35 (s, 1H), 3.26 (s, 1H), 3.10 (s, 3H),    3.06 (d, 1H, J=8.8 Hz), 2.73 (d, 1H, J=8.8 Hz), 2.21 (s, 3H), 1.82    (d, 1H, J=9.1 Hz), 1.72 (d, 1H, J=9.1 Hz; LCMS: purity: 99%; MS    (m/e): 430 (MH⁺);-   4-(6-(3-ethoxypropyl)aminopyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #186, LCMS: purity: 99%; MS (m/e): 474 (MH⁺);-   4-(6-(cis-2,6-dimethylmorpholin-4-yl)pyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #187, ¹H NMR (DMSO-d₆): δ 9.20 (s, 1H), 8.89 (d, 1H, J=2.3    Hz), 8.34 (d, 1H, J=5.3 Hz), 8.24 (dd, 1H, J=2.3 and 9.1 Hz), 7.48    (d, 1H, J=9.1 Hz), 7.44 (s, 1H), 7.21 (d, 1H, J=5.3 Hz), 6.97 (d,    1H, J=9.1 Hz), 6.74 (d, 1H, J=9.1 Hz), 4.30-4.26 (m, 2H), 3.88 (s,    1H), 3.61-3.56 (m, 2H), 3.21-3.13 (m, 2H), 2.73 (app qt, 2H, J=9.1    Hz), 2.27 (s, 3H), 2.18 (s, 3H), 1.77 (d, 1H, J=9.0 Hz), 1.68 (d,    1H, J=9.0 Hz), 1.15 (d, 6H, J=6.2 Hz); LCMS: purity: 99%; MS (m/e):    486 (MH⁺);-   4-(6-(propylamino)pyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #188, ¹H NMR (DMSO-d₆): δ 9.14 (s, 1H), 8.78 (s, 1H), 8.30    (d, 1H, J=5.3 Hz), 8.06 (d, 1H, J=8.8 Hz), 7.49 (d, 1H, J=8.5 Hz),    7.43 (s, 1H), 7.13-7.12 (m, 2H), 6.75 (d, 1H, J=8.8 Hz), 6.54 (d,    1H, J=8.8 Hz), 3.89 (s, 1H), 3.28-3.14 (m, 5H), 2.76-2.79 (m, 2H),    2.29 (s, 3H), 2.18 (s, 3H), 1.79 (d, 1H, J=9.1 Hz), 1.69 (d, 1H,    J=9.1 Hz), 1.60-1.48 (m, 2H), 0.90 (t, 3H, J=7.3 Hz); LCMS: purity:    99%; MS (m/e): 430 (MH⁺);-   4-(6-(2-(dimethylamino)methylmorpholin-4-yl)pyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #189, ¹H NMR (DMSO-d₆): δ 9.20 (s, 1H), 8.90 (s, 1H), 8.35    (d, 1H, J=4.9 Hz), 8.25 (app d, 1H, J=8.8 Hz), 7.48 (d, 1H, J=8.5    Hz), 7.43 (s, 1H), 7.21 (d, 1H, J=4.9 Hz), 6.94 (d, 1H, J=8.5 Hz),    6.74 (d, 1H, J=8.8 Hz), 4.34 (d, 1H, J=12.4 Hz), 4.14 (d, 1H, J=12.4    Hz), 3.94-2.88 (m, 2H), 3.57-3.49 (m, 2H), 3.21-3.10 (m, 3H),    2.96-2.92 (m, 1H), 2.74-2.58 (m, 3H), 2.41-2.30 (m, 2H), 2.30 (s,    3H), 2.18 (overlap s, 9H), 1.77 (d, 1H, J=9.1 Hz), 1.68 (d, 1H,    J=9.1 Hz); LCMS: purity: 99%; MS (m/e): 515 (MH⁺);-   4-(6-(piperidin-1-yl)pyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #190, ¹H NMR (DMSO-d₆): δ 9.17 (s, 1H), 8.86 (s, 1H), 8.33    (d, 1H, J=5.3 Hz), 8.20-8.17 (d, 1H, J=9.1 Hz), 7.49 (d, 1H, J=8.8    Hz), 7.43 (s, 1H), 7.17 (d, 1H, J=5.3H), 6.91 (d, 1H, J=8.8 Hz),    6.73 (d, 1H, J=8.8 Hz), 3.87 (s, 1H), 3.62 (br s, 4H), 3.29 (s, 1H),    3.21-3.12 (m, 2H), 2.72 (d, 1H, J=9.1 Hz), 2.66 (d, 1H, J=9.1 Hz),    2.26 (s, 3H), 2.18 (s, 3H), 1.77-1.52 (m, 8H); LCMS: purity: 99%; MS    (m/e): 456 (MH⁺);-   4-(6-(3-(aminocarbonyl)piperidin-1-yl)pyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #191, LCMS: purity: 99%; MS (m/e): 499 (MH⁺);-   4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-methylsulfonyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #192, ¹H NMR (DMSO-d₆): δ 9.48 (s, 1H), 8.92 (s, 1H), 8.35    (s, 1H), 8.29 (d, 1H, J=8.8 Hz), 7.47 (app s, 2H), 7.28 (s, 1H),    7.01 (d, 1H, J=9.1 Hz), 6.91 (d, 1H, J=8.8 Hz), 4.35 (s, 1H), 4.18    (s, 1H), 3.68 (br s, 4H), 3.60 (br s, 4H), 3.40-3.37 (m, 4H), 2.96    (s, 3H), 2.21 (s, 3H), 1.90-1.85 (m, 2H); LCMS: purity: 99%; MS    (m/e): 522 (MH⁺);-   4-(4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(3-methyl-4-((1S,4S)-5-methylsulfonyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #193, ¹H NMR (DMSO-d₆): δ 9.37 (s, 1H), 8.51 (s, 1H), 8.32    (d, 1H, J=4.3 Hz), 7.64 (s, 1H), 7.48 (s, 2H), 7.23 (d, 1H, J=4.3    Hz), 6.89 (d, 1H, J=8.8 Hz), 4.34 (s, 1H), 4.23-4.17 (m, 3H), 3.53    (s, 2H), 3.42-3.23 (m, 4H), 3.12 (s, 3H), 2.95 (s, 3H), 2.21 (s,    3H), 1.91 (d, 1H, J=9.1 Hz), 1.82 (d, 1H, J=9.1 Hz); LCMS: purity:    99%; MS (m/e): 508 (MH⁺);-   4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-oxa-2-azabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #194, ¹H NMR (DMSO-d₆): δ 9.24 (s, 1H), 8.91 (s, 1H), 8.36    (d, 1H, J=5.3 Hz), 8.25 (d, 1H, J=9.1 Hz), 7.52-7.47 (m, 2H), 7.22    (d, 1H, J=5.2 Hz), 6.95 (d, 1H, J=9.1 Hz), 6.80 (d, 1H, J=8.5 Hz),    4.50 (s, 1H), 4.12 (s, 1H), 3.89 (d, 1H, J=7.3 Hz), 3.69-3.67 (br m,    5H), 3.57 (br m, 5H), 3.04 (d, 1H, J=9.6 Hz), 2.18 (s, 3H), 1.87 (d,    1H, J=8.5 Hz), 1.75 (d, 1H, J=8.5 Hz); LCMS: purity: 99%; MS (m/e):    445 (MH⁺);-   4-(4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(3-methyl-4-((1S,4S)-5-oxa-2-azabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #195, ¹H NMR (DMSO-d₆): δ 9.23 (s, 1H), 8.51 (d, 1H, J=1.8    Hz), 8.32 (d, 1H, J=5.3 Hz), 7.62 (d, 1H, J=1.8 Hz), 7.47 (s, 2H),    7.19 (d, 1H, J=5.3 Hz), 6.81 (d, 1H, J=9.1 Hz), 4.51 (s, 1H),    4.24-4.21 (m, 2H), 4.14 (s, 1H), 3.89 (d, 1H, J=7.3 Hz), 3.70 (d,    1H, J=7.3 Hz), 3.53-3.50 (m, 2H), 3.33 (d, 1H, J=9.1 Hz), 3.11 (s,    3H), 3.06 (d, 1H, J=8.2 Hz), 2.18 (s, 3H), 1.87 (d, 1H, J=9.1 Hz),    1.76 (d, 1H, J=9.1 Hz); LCMS: purity: 99%; MS (m/e): 431 (MH⁺);-   4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-ethylcarbonyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #196, ¹H NMR (DMSO-d₆): δ 9.24 (s, 1H), 8.92 (d, 1H, J=2.0    Hz), 8.36 (d, 1H, J=5.3 Hz), 8.25 (dd, 1H, J=2.3 and 9.1 Hz),    7.52-7.47 (m, 2H), 7.22 (d, 1H, J=5.3 Hz), 6.95 (d, 1H, J=8.8 Hz),    6.81 (app t, 1H, J=8.8 Hz), 4.68 (s, 0.5H), 4.55 (s, 0.5 Hz), 4.17    (s, 0.5H), 4.11 (s, 0.5 Hz), 3.69-3.59 (m, 4H), 3.56-3.55 (m, 4H),    3.51-3.43 (m, 3H), 3.37-3.30 (m, 1H), 3.13-3.03 (m, 1H), 2.36-2.25    (m, 1H), 2.18 (s, 3H), 2.13-2.10 (m, 1H), 1.96-1.73 (m, 2H), 0.97    (t, 3H, J=7.6 Hz); LCMS: purity: 99%; MS (m/e): 500 (MH⁺);-   4-(6-(2-(morpholin-4-yl)ethyl)aminopyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-ethylcarbonyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #197, LCMS: purity: 99%; MS (m/e): 543 (MH⁺);-   4-(6-(3-dimethylamino)propylaminopyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #198, ¹H NMR (DMSO-d₆) δ 9.11 (s, 1H), 8.79 (d, 1H, J=2.0    Hz), 8.30 (d, 1H, J=5.3 Hz), 8.06 (dd, 1H, J=2.3 and 9.1 Hz),    7.48-7.45 (m, 2H), 7.13-7.09 (m, 2H), 6.75 (d, 1H, J=8.8 Hz), 6.54    (d, 1H, J=8.8 Hz), 3.88 (s, 1H), 3.30 (m, 3H), 3.22-3.14 (m, 2H),    2.75-2.66 (m, 2H), 2.27-2.24 (m, 5H), 2.18 (s, 3H), 2.12 (s, 6H),    1.79-1.62 (m, 4H); LCMS: purity: 99%; MS (m/e): 473 (MH⁺);-   4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-amidino-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #199, ¹H NMR (DMSO-d₆): δ 9.32 (s, 1H), 8.92 (s, 1H), 8.37    (d, 1H, J=5.3 Hz), 8.25 (d, 1H, J=9.1 Hz), 7.55 (d, 1H, J=9.1 Hz),    7.51 (s, 1H), 7.31 (s, 2H), 7.24 (d, 1H, J=5.3 Hz), 7.17 (br s, 1H),    6.96 (d, 1H, J=8.8 Hz), 6.83 (d, 1H, J=8.8 Hz), 4.70 (s, 1H), 4.28    (s, 1H), 3.69-3.68 (br m, 4H), 3.57-3.56 (br m, 4H), 3.51-3.40 (m,    3H), 3.17 (d, 1H, J=9.3 Hz), 2.20 (s, 3H), 2.06-1.93 (m, 2H); LCMS:    purity: 92%; MS (m/e): 486 (MH⁺-TFA);-   4-(6-(3-ethoxypropyl)aminopyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-oxa-2-azabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #200, ¹H NMR (DMSO-d₆): δ 9.17 (s, 1H), 8.80 (d, 1H, J=2.3    Hz), 8.31 (d, 1H, J=5.3 Hz), 8.07 (dd, 1H, J=2.3 and 8.8 Hz), 7.51    (d, 1H, J=8.8 Hz), 7.46 (d, 1H, J=2.0 Hz), 7.14-7.09 (m, 2H), 6.80    (d, 1H, J=8.8 Hz), 6.54 (d, 1H, J=8.8 Hz), 4.50 (s, 1H), 4.11 (s,    1H), 3.89 (d, 1H, J=7.3 Hz), 3.70 (d, 1H, J=7.3 Hz), 3.41-3.29 (m,    7H), 3.04 (d, 1H, J=9.3 Hz), 2.17 (s, 3H), 1.86 (d, 1H, J=7.3 Hz),    1.78-1.73 (m, 3H), 1.09 (t, 3H, J=7.3 Hz); LCMS: purity: 99%; MS    (m/e): 461 (MH⁺);-   4-(6-cis-2,6-dimethylmorpholin-4-yl)pyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-oxa-2-azabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #201, LCMS: purity: 99%; MS (m/e): 473 (MH⁺);-   4-(6-(propylamino)pyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-oxa-2-azabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #202, ¹H NMR (DMSO-d₆): δ 9.20 (s, 1H), 8.76 (s, 1H), 8.32    (d, 1H, J=4.7 Hz), 8.11 (d, 1H, J=8.8 Hz), 7.51-7.49 (m, 1H), 7.45    (s, 1H), 7.32 (m, 1H), 7.15 (s, 1H), 6.80 (d, 1H, J=8.8 Hz), 6.60    (d, 1H, J=8.8 Hz), 4.50 (s, 1H), 4.12 (s, 1H), 3.89 (d, 1H, J=7.3    Hz), 3.70 (d, 1H, J=7.3 Hz), 3.32-3.24 (m, 3H), 3.04 (d, 1H, J=8.8    Hz), 2.17 (s, 3H), 1.86 (d, 1H, J=7.3 Hz), 1.76 (d, 1H, J=8.8 Hz),    1.55-1.49 (m, 2H), 0.91 (t, 3H, J=7.3 Hz); LCMS: purity: 99%; MS    (m/e): 417 (MH⁺);-   4-(6-(3-dimethylamino)propylaminopyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-oxa-2-azabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #203, ¹H NMR (DMSO-d₆): δ 9.17 (s, 1H), 8.80 (s, 1H), 8.31    (d, 1H, J=5.3 Hz), 8.07 (dd, 1H, J=2.3 and 9.1 Hz), 7.51 (d, 1H,    J=8.8 Hz), 7.46 (s, 1H), 7.14-7.13 (m, 2H), 6.80 (d, 1H, J=8.5 Hz),    6.53 (d, 1H, J=8.8 Hz), 4.50 (s, 1H), 4.12 (s, 1H), 3.89 (d, 1H,    J=7.3 Hz), 3.70 (d, 1H, J=7.3 Hz), 3.30-3.26 (m, 4H), 3.03 (d, 1H,    J=8.8 Hz), 2.27 (t, 2H, J=7.0 Hz), 2.17 (s, 3H), 2.11 (s, 6H), 1.87    (d, 1H, J=7.3 Hz), 1.76 (d, 1H, J=8.5 Hz), 1.65 (q, 2H, J=7.0 Hz);    LCMS: purity: 99%; MS (m/e): 460 (MH⁺);-   4-(6-(1,4-oxazepan-4-yl)pyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-oxa-2-azabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #204, ¹H NMR (DMSO-d₆): δ 9.20 (s, 1H), 8.87 (d, 1H, J=2.0    Hz), 8.33 (d, 1H, J=5.3 Hz), 8.21 (d, 1H, J=2.0 and 8.8 Hz), 7.53    (app d, 1H, J=8.8 Hz), 7.45 (d, 1H, J=2.0 Hz), 7.19 (d, 1H, J=5.3    Hz), 6.82 (d, 1H, J=8.8 Hz), 6.80 (d, 1H, J=8.8 Hz), 4.50 (s, 1H),    4.12 (s, 1H), 3.90-3.65 (m, 7H), 3.59 (t, 2H, J=5.8 Hz), 3.05-2.97    (m, 2H), 2.18 (s, 3H), 1.87-1.73 (m, 2H), 1.14 (t, 2H, J=7.3 Hz);    LCMS: purity: 99%; MS (m/e): 459 (MH⁺);-   4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-isobutyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #205, ¹H NMR (DMSO-d₆): δ 9.19 (s, 1H), 8.91 (s, 1H), 8.35    (d, 1H, J=5.3 Hz), 8.25 (dd, 1H, J=2.3 and 8.8 Hz), 7.47-7.44 (app    m, 2H), 7.20 (d, 1H, J=5.3 Hz), 6.95 (d, 1H, J=8.8 Hz), 6.72 (d, 1H,    J=8.8 Hz), 3.89 (s, 1H), 3.70-3.68 (m, 4H), 3.59-3.57 (m, 4H), 3.36    (s, 1H), 3.21-3.14 (m, 2H), 2.80 (d, 1H, J=9.1 Hz), 2.66 (d, 1H,    J=8.5 Hz), 2.31-2.22 (m, 2H), 2.18 (s, 3H), 1.70 (d, 1H, J=8.5 Hz),    1.66 (d, 1H, J=9.1 Hz), 1.56-1.52 (m, 1H), 0.83 (d, 6H, J=6.4 Hz),    LCMS: purity: 99%; MS (m/e): 500 (MH⁺);-   4-(6-(1,4-oxazepan-4-yl)pyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #206, ¹H NMR (DMSO-d₆): δ 9.16 (s, 1H), 8.87 (d, 1H, J=2.0    Hz), 8.33 (d, 1H, J=5.3 Hz), 8.22 (dd, 1H, J=2.3 and 9.1 Hz), 7.50    (d, 1H, J=8.8 Hz), 7.42 (d, 1H, J=2.3 Hz), 7.18 (d, 1H, J=5.3 Hz),    6.82 (d, 1H, J=8.8 Hz), 6.74 (d, 1H, J=8.8 Hz), 3.87 (s, 1H),    3.82-3.71 (m, 6H), 3.61-3.57 (m, 2H), 3.21-3.12 (m, 2H), 2.73 (d,    1H, J=9.1 Hz), 2.66 (d, 1H, J=9.1 Hz), 2.62 (s, 3H), 2.18 (s, 3H),    1.91-1.83 (m, 2H), 1.76 (d, 1H, J=9.1 Hz), 1.68 (d, 1H, J=9.1 Hz);    LCMS: purity: 99%; MS (m/e): 472 (MH⁺);-   4-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(3-methyl-4-(1,5,7-trimethyl-3,7-diazabicyclo[3.3.1]nonan-3-yl)phenyl)pyrimidin-2-amine,    compound #207, ¹H NMR (DMSO-d₆): δ 11.51 (s, 1H), 9.57 (s, 1H), 8.75    (d, 1H, J=2.0 Hz), 8.50 (d, 1H, J=5.3 Hz), 8.04 (d, 1H, J=2.0 Hz),    7.66 (d, 1H, J=2.0 Hz), 7.59 (dd, 1H, J=2.0 and 8.8 Hz), 7.41 (d,    1H, J=5.3 Hz), 7.11 (d, 1H, J=8.8 Hz), 3.53 (d, 2H, J=10.8 Hz), 3.03    (d, 2H, J=10.8 Hz), 2.94-2.85 (app t, 2H, J=9.9 Hz), 2.75 (s, 3H),    2.67 (d, 2H, J=10.8 Hz), 2.31 (s, 3H), 1.54-1.46 (m, 2H), 1.45 (s,    6H), 0.92 (s, 6H); LCMS: purity: 99%; MS (m/e): 528 (MH⁺);-   4-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(3-fluoro-4-(1,5,7-trimethyl-3,7-diazabicyclo[3.3.1]nonan-3-yl)phenyl)pyrimidin-2-amine,    compound #208, ¹H NMR (DMSO-d₆): δ 11.53 (s, 1H), 9.79 (s, 1H), 8.75    (d, 1H, J=2.0 Hz), 8.53 (d, 1H, J=5.3 Hz), 8.04 (d, 1H, J=1.7 Hz),    7.85 (dd, 1H, J=2.3 and 17.0 Hz), 7.46-7.41 (m, 2H), 7.09 (t, 1H,    J=9.1 Hz), 3.44 (d, 2H, J=11.4 Hz), 3.15 (d, 2H, J=10.8 Hz),    2.94-2.87 (t, 2H, J=9.9 Hz), 2.75 (s, 3H), 2.67 (d, 2H, J=10.8 Hz),    1.54-1.39 (m, 2H), 1.46 (s, 6H), 0.92 (s, 6H); LCMS: purity: 99%; MS    (m/e): 532 (MH⁺);-   4-(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #209, ¹H NMR (DMSO-d₆): δ 11.53 (s, 1H), 9.16 (s, 1H), 8.55    (d, 1H, J=2.0 Hz), 8.31 (d, 1H, J=5.3 Hz), 7.62 (s, 1H), 7.47-7.42    (m, 2H), 7.18 (d, 1H, J=5.3 Hz), 6.73 (d, 1H, J=8.5 Hz), 4.29 (s,    2H), 3.81 (s, 1H), 3.21-3.14 (m, 3H), 2.72 (d, 1H, J=9.1 Hz), 2.66    (d, 1H, J=9.1 Hz), 2.26 (s, 3H), 2.19 (s, 3H), 1.76 (d, 1H, J=9.1    Hz), 1.68 (d, 1H, J=9.1 Hz); LCMS: purity: 99%; MS (m/e): 444 (MH⁺);-   4-(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(3-methyl-4-((1S,4S)-5-oxa-2-azabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #210, ¹H NMR (DMSO-d₆): δ 11.53 (s, 1H), 9.35 (s, 1H), 8.70    (d, 1H, J=1.8 Hz), 8.45 (d, 1H, J=5.3 Hz), 7.99 (d, 1H, J=1.8 Hz),    7.49 (s, 1H), 7.45 (d, 1H, J=8.8 Hz), 7.33 (d, 1H, J=5.3 Hz), 6.80    (d, 1H, J=8.8 Hz), 4.72 (s, 2H), 4.50 (s, 1H), 4.13 (s, 1H), 3.89    (d, 1H, J=7.3 Hz), 3.71 (d, 1H, J=7.3 Hz), 3.04 (d, 1H, J=9.3 Hz),    2.18 (s, 3H), 1.86 (d, 1H, J=9.3 Hz), 1.75 (d, 1H, J=9.3 Hz), LCMS:    purity: 99%; MS (m/e): 431 (MH⁺);-   4-(6-(3-ethoxypropyl)aminopyridin-3-yl)-N-(3-methyl-4-(1,5,7-trimethyl-3,7-diazabicyclo[3.3.1]nonan-3-yl)phenyl)pyrimidin-2-amine,    compound #211, ¹H NMR (DMSO-d₆): δ 9.19 (s, 1H), 8.79 (s, 1H), 8.32    (d, 1H, J=4.9 Hz), 8.08 (d, 1H, J=2.6 and 9.1 Hz), 7.52 (d, 1H,    J=9.1 Hz), 7.48 (s, 1H), 7.16-7.11 (m, 2H), 6.86 (d, 1H, J=8.8 Hz),    6.54 (d, 1H, J=8.8 Hz), 3.44-3.32 (m, 6H), 3.15-3.13 (m, 2H), 2.85    (d, 2H, J=9.6 Hz), 2.71 (d, 2H, J=9.6 Hz), 2.30 (s, 3H), 2.13-2.11    (m, 1H), 2.08 (s, 3H), 1.80-1.73 (m, 5H), 1.10 (t, 3H, J=7.3 Hz),    0.82 (s, 6H); LCMS: purity: 99%; MS (m/e): 530 (MH⁺);-   4-(6-((2S,6R)-2,6-dimethylmorpholin-4-yl)pyridin-3-yl)-N-(3-methyl-4-(1,5,7-trimethyl-3,7-diazabicyclo[3.3.1]nonan-3-yl)phenyl)pyrimidin-2-amine,    compound #212, LCMS: purity: 99%; MS (m/e): 542 (MH⁺);-   4-(6-(propylamino)pyridin-3-yl)-N-(3-methyl-4-(1,5,7-trimethyl-3,7-diazabicyclo[3.3.1]nonan-3-yl)phenyl)pyrimidin-2-amine,    compound #213, ¹H NMR (DMSO-d₆): δ 9.18 (s, 1H), 8.78 (s, 1H), 8.32    (d, 1H, J=5.3 Hz), 8.07 (dd, 1H, J=2.6 and 9.1 Hz), 7.54 (d, 1H,    J=8.2 Hz), 7.48 (s, 1H), 7.16-7.11 (m, 2H), 6.86 (d, 1H, J=8.2 Hz),    6.54 (d, 1H, J=9.1 Hz), 3.26-3.24 (m, 2H), 2.85 (d, 2H, J=10.2 Hz),    2.70 (d, 2H, J=12.5 Hz), 2.30 (s, 3H), 2.08 (s, 3H), 1.76 (d, 2H,    J=9.6 Hz), 1.54 (q, 2H, J=7.3 Hz), 1.19-1.03 (m, 2H), 0.09 (t, 3H,    J=7.3 Hz), 0.82 (s, 6H); LCMS: purity: 99%; MS (m/e): 486 (MH⁺);-   4-(6-(3-dimethylamino)propylaminopyridin-3-yl)-N-(3-methyl-4-(1,5,7-trimethyl-3,7-diazabicyclo[3.3.1]nonan-3-yl)phenyl)pyrimidin-2-amine,    compound #214, ¹H NMR (DMSO-d₆): δ 9.18 (s, 1H), 8.78 (d, 1H, J=2.3    Hz), 8.32 (d, 1H, J=5.3 Hz), 8.07 (dd, 1H, J=2.3 and 8.8 Hz), 7.52    (d, 1H, J=8.5 Hz), 7.49 (d, 1H, J=2.3 Hz), 7.15-7.09 (m, 2H), 6.85    (d, 1H, J=8.5 Hz), 6.54 (d, 1H, J=8.8 Hz), 2.86 (d, 2H, J=10.8 Hz),    2.71 (d, 2H, J=10.8 Hz), 2.30 (s, 3H), 2.25-2.23 (m, 3H), 2.11 (s,    6H), 2.08 (s, 3H), 1.78 (d, 2H, J=9.5 Hz), 1.68 (q, 2H, J=7.3 Hz),    1.19 (d, 1H, J=12.0 Hz), 1.07 (d, 1H, J=12.0 Hz), 0.82 (s, 6H);    LCMS: purity: 99%; MS (m/e): 529 (MH⁺);-   4-(6-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)pyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #215, ¹H NMR (DMSO-d₆): δ 9.16 (s, 1H), 8.87 (d, 1H, J=2.3    Hz), 8.33 (d, 1H, J=5.3 Hz), 8.21 (dd, 1H, J=2.0 and 8.8 Hz), 7.49    (d, 1H, J=9.1 Hz), 7.43 (d, 1H, J=5.3 Hz), 7.18 (d, 1H, J=5.3 Hz),    7.74 (d, 1H, J=8.8 Hz), 6.64 (d, 1H, J=8.8 Hz), 4.95 (s, 1H), 4.67    (s, 1H), 3.88 (s, 1H), 3.79 (d, 1H, J=6.7 Hz), 3.65 (d, 1H, J=7.6    Hz), 3.50 (d, 1H, J=10.3 Hz), 3.21-3.12 (m, 2H), 2.73 (d, 1H, J=9.4    Hz), 2.67 (d, 1H, J=9.4 Hz), 2.27 (s, 3H), 2.19 (s, 3H), 1.93 (d,    1H, J=9.4 Hz), 1.87 (d, 1H, J=9.4 Hz), 1.77 (d, 1H, J=9.1 Hz), 1.68    (d, 1H, J=9.1 Hz); LCMS: purity: 99%; MS (m/e): 470 (MH⁺);-   4-(6-((1S,4S)-5-oxa-2-azabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-oxa-2-azabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #216, ¹H NMR (DMSO-d₆): δ 9.19 (s, 1H), 8.86 (s, 1H), 8.33    (d, 1H, J=5.3 Hz), 8.21 (dd, 1H, J=2.0 and 8.8 Hz), 7.52 (d, 1H,    J=8.5 Hz), 7.45 (s, 1H), 7.18 (d, 1H, J=5.3 Hz), 6.81 (d, 1H, J=8.5    Hz), 6.62 (d, 1H, J=8.8 Hz), 4.95 (s, 1H), 4.68 (s, 1H), 4.50 (s,    1H), 4.12 (s, 1H), 3.89 (d, 1H, J=7.3 Hz), 3.79 (d, 1H, J=7.3 Hz),    3.70 (d, 1H, J=7.0 Hz), 3.49 (d, 1H, J=9.9 Hz), 3.2 (d, 1H, J=9.9    Hz), 3.04 (d, 1H, J=9.6 Hz), 2.18 (s, 3H), 1.94-1.85 (m, 3H), 1.75    (d, 1H, J=9.1 Hz); LCMS: purity: 99%; MS (m/e): 457 (MH⁺);-   4-(6-(3-methylbutyl)aminopyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #217, ¹H NMR (DMSO-d₆): δ 9.12 (s, 1H), 8.79 (d, 1H, J=2.3    Hz), 8.29 (d, 1H, J=4.7 Hz), 8.06 (dd, 1H, J=2.3 and 8.8 Hz), 7.47    (d, 1H, J=8.8 Hz), 7.43 (d, 1H, J=2.3 Hz), 7.12 (d, 1H, J=4.7 Hz),    7.06 (t, 1H, J=5.3 Hz), 6.74 (d, 1H, J=8.8 Hz), 6.53 (d, 1H, J=8.8    Hz), 3.87 (s, 1H), 3.21-3.12 (m, 2H), 2.72 (d, 1H, J=9.3 Hz), 2.66    (d, 1H, J=9.3 Hz), 2.26 (s, 3H), 2.18 (s, 3H), 1.73 (d, 1H, J=8.5    Hz), 1.69-1.63 (m, 2H), 1.46-1.39 (app qt, 2H, J=7.3 Hz), 0.89 (d,    6H, J=6.7 Hz); LCMS: Purity: 99%; MS (m/e): 458 (MH⁺);-   4-(6-(3,3-dimethylbutyl)aminopyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #218, ¹H NMR (DMSO-d₆): δ 9.12 (s, 1H), 8.79 (d, 1H, J=2.3    Hz), 8.30 (d, 1H, J=5.3 Hz), 8.06 (dd, 1H, J=2.3 and 8.8 Hz), 7.48    (d, 1H, J=8.5 Hz), 7.43 (d, 1H, J=2.3 Hz), 7.13 (d, 1H, J=5.3 Hz),    7.01 (t, 1H, J=5.3 Hz), 6.74 (d, 1H, J=8.5 Hz), 6.51 (d, 1H, J=9.1    Hz), 3.88 (s, 1H), 3.16-3.12 (m, 2H), 2.73 (d, 1H, J=9.3 Hz), 2.68    (d, 1H, J=9.3 Hz), 2.27 (s, 3H), 2.18 (s, 3H), 1.77 (d, 1H, J=9.3    Hz), 1.68 (d, 1H, J=9.3 Hz), 1.49-1.43 (m, 2H), 0.92 (s, 9H); LCMS:    Purity: 99%; MS (m/e): 472 (MH⁺);-   4-(6-(2-methoxyethyl)(methyl)aminopyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #219, ¹H NMR (DMSO-d₆): δ 9.16 (s, 1H), 8.86 (d, 1H, J=2.3    Hz), 8.32 (d, 1H, J=5.3 Hz), 8.20 (dd, 1H, J=2.3 and 9.1 Hz), 7.49    (d, 1H, J=8.5 Hz), 7.43 (d, 1H, J=2.3 Hz), 7.18 (d, 1H, J=5.3 Hz),    6.77 (d, 1H, J=9.1 Hz), 6.74 (d, 1H, J=8.5 Hz), 3.88 (s, 1H), 3.75    (t, 2H, J=5.8 Hz), 3.51 (t, 2H, J=5.3 Hz), 3.23 (app s, 3H),    3.18-3.12 (m, 2H), 3.08 (s, 3H), 2.73 (d, 1H, J=9.1 Hz), 2.66 (d,    1H, J=9.1 Hz), 2.26 (s, 3H), 2.18 (s, 3H), 1.77 (d, 1H, J=9.4 Hz),    1.68 (d, 1H, J=9.3 Hz). LCMS: Purity: 99%; MS (m/e): 460 (MH⁺);-   4-(6-(2-methoxyethyl)(methyl)aminopyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-oxa-2-azabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #220, ¹H NMR (DMSO-d₆): δ 9.19 (s, 1H), 8.87 (d, 1H, J=2.3    Hz), 8.33 (d, 1H, J=5.3 Hz), 8.20 (dd, 1H, J=2.3 and 9.1 Hz), 7.53    (d, 1H, J=9.1 Hz), 7.45 (d, 1H, J=2.3 Hz), 6.81 (d, 1H, J=9.1 Hz),    6.75 (d, 1H, J=9.1 Hz), 4.50 (s, 1H), 4.12 (s, 1H), 3.89 (d, 1H,    J=7.3 Hz), 3.78-3.69 (m, 3H), 3.51 (t, 3H, J=5.3 Hz), 3.23 (s, 3H),    3.08 (s, 3H), 3.03 (d, 1H, J=9.6 Hz), 2.18 (s, 3H), 1.87 (d, 1H,    J=9.1 Hz), 1.75 (d, 1H, J=9.1 Hz); LCMS: Purity: 99%; MS (m/e): 447    (MH⁺);-   4-(6-(2-methoxyethyl)(methyl)aminopyridin-3-yl)-N-(3-methyl-4-(1,5,7-trimethyl-3,7-diazabicyclo[3.3.1]nonan-3-yl)phenyl)pyrimidin-2-amine,    compound #221, ¹H NMR (DMSO-d₆): δ 9.23 (s, 1H), 8.87 (d, 1H, J=2.3    Hz), 8.34 (d, 1H, J=5.3 Hz), 8.20 (dd, 1H, J=2.3 and 9.1 Hz), 7.55    (d, 1H, J=8.5 Hz), 7.48 (d, 1H, J=2.3 Hz), 7.20 (d, 1H, J=5.3 Hz),    6.86 (d, 1H, J=8.8 Hz), 6.76 (d, 1H, J=9.1 Hz), 3.76 (t, 2H, J=5.3    Hz), 3.51 (t, 2H, J=5.3 Hz), 3.23 (s, 3H), 3.08 (s, 3H), 2.85 (d,    2H, J=10.8 Hz), 2.70 (d, 2H, J=10.8 Hz), 2.31 (s, 3H), 2.07 (s, 3H),    1.76 (d, 2H, J=11.4 Hz), 1.19-1.02 (m, 2H), 0.82 (s, 6H); LCMS:    Purity: 99%; MS (m/e): 516 (MH⁺);-   4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-methyl-4-((1S,4R)-2-azabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #222, ¹H NMR (DMSO-d₆): δ 9.17 (s, 1H), 8.91 (d, 1H, J=2.3    Hz), 8.34 (d, 1H, J=5.3 Hz), 8.25 (d, 1H, J=2.3 and 8.8 Hz), 7.45    (d, 1H, J=8.5 Hz), 7.41 (d, 1H, J=2.0 Hz), 7.20 (d, 1H, J=5.3 Hz),    6.95 (d, 1H, J=8.8 Hz), 6.73 (d, 1H, J=8.8 Hz), 3.81 (s, 1H),    3.69-3.67 (m, 4H), 3.57-3.55 (m, 4H), 2.75 (d, 1H, J=8.5 Hz), 2.18    (s, 3H), 1.81-1.56 (m, 4H), 1.38-1.29 (m, 2H); LCMS: Purity: 99%; MS    (m/e): 443 (MH⁺);-   4-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(3-methyl-4-((1S,4R)-2-azabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #223, LCMS: Purity: 99%; MS (m/e): 457 (MH⁺);-   4-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(3-methyl-4-(2-methylsulfonyl-2-azabicyclo[2.2.1]heptan-5-yl)phenyl)pyrimidin-2-amine    and    4-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(3-methyl-4-(2-methylsulfonyl-2-azabicyclo[2.2.1]heptan-6-yl)phenyl)pyrimidin-2-amine    (68:31), compound #224, Mixture: LCMS: Purity: 99% (68:31); MS    (m/e): 521 (MH⁺);    4-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(3-methyl-4-(2-methylsulfonyl-2-azabicyclo[2.2.1]heptan-5-yl)phenyl)pyrimidin-2-amine    ¹H NMR (DMSO-d₆): δ 11.50 (s, 1H), 9.52 (s, 1H), 8.75 (d, 1H, J=2.3    Hz), 8.49 (d, 1H, J=5.3 Hz), 8.04 (d, 1H, J=2.3 Hz), 7.62 (s, 1H),    7.55 (dd, 1H, J=2.3 and 8.5 Hz), 7.39 (d, 1H, J=5.3 Hz), 7.13 (d,    1H, J=8.5 Hz), 4.10 (s, 1H), 3.26-3.25 (m, 1H), 3.12-3.05 (m, 2H),    2.91 (s, 3H), 2.62 (s, 1H), 2.27 (s, 3H), 2.20-2.17 (m, 1H),    1.70-1.60 (m, 3H), 1.45 (s, 6H); LCMS: Purity: 95%; MS (m/e): 535    (MH⁺);-   4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-methyl-4-(2-methylsulfonyl-2-azabicyclo[2.2.1]heptan-5-yl)phenyl)pyrimidin-2-amine    and    4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-methyl-4-(2-methylsulfonyl-2-azabicyclo[2.2.1]heptan-6-yl)phenyl)pyrimidin-2-amine    (85:15), compound #225, Mixture: LCMS: Purity: 97% (85:15); MS    (m/e): 521 (MH⁺);-   4-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(4-(2-methylsulfonyl-2-azabicyclo[2.2.1]heptan-5-yl)phenyl)pyrimidin-2-amine,    compound #226, ¹H NMR (DMSO-d₆): δ 11.51 (s, 1H), 9.61 (s, 1H), 8.74    (d, 1H, J=1.8 Hz), 8.50 (d, 1H, J=4.3 Hz), 8.03 (s, 1H), 7.70-7.69    (d, 2H, J=8.8 Hz), 7.40 (d, 1H, J=4.3 Hz), 7.20 (d, 1H, J=8.5 Hz),    4.10 (s, 1H), 3.26-3.23 (m, 1H), 3.09-2.99 (m, 2H), 2.90 (s, 3H),    2.58 (s, 1H), 2.20-2.13 (m, 1H), 1.79-1.53 (m, 3H), 1.45 (s, 6H);    LCMS: Purity: 96%; MS (m/e): 521 (MH⁺);-   4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(4-(2-methylsulfonyl-2-azabicyclo[2.2.1]heptan-5-yl)phenyl)pyrimidin-2-amine,    compound #227, ¹H NMR (DMSO-d₆): δ 9.62 (s, 1H), 8.90 (s, 1H), 8.43    (d, 1H, J=5.5 Hz), 8.32 (app d, 2H, J=9.1 Hz), 7.72-7.69 (m, 2H),    7.33 (d, 1H, J=5.5 Hz), 7.20 (d, 1H, J=8.8 Hz), 7.04 (d, 1H, J=9.1    Hz), 4.11 (s, 1H), 3.71-3.69 (m, 4H), 3.62-3.60 (m, 4H), 3.25-3.22    (m, 1H), 3.10-2.99 (m, 2H), 2.90 (s, 3H), 2.59 (s, 1H), 2.20-2.13    (m, 1H), 1.78-1.54 (m, 3H); LCMS: Purity: 96%; MS (m/e): 507 (MH⁺);-   4-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(4-(2-methylsulfonyl-2-azabicyclo[2.2.1]heptan-6-yl)phenyl)pyrimidin-2-amine,    compound #228, ¹H NMR (DMSO-d₆): δ 11.51 (s, 1H), 9.64 (s, 1H), 8.74    (d, 1H, J=1.8 Hz), 8.50 (d, 1H, J=5.3 Hz), 8.03 (d, 1H, J=1.8 Hz),    7.72 (d, 2H, J=8.8 Hz), 7.41 (d, 1H, J=5.3 Hz), 7.17 (d, 2H, J=8.8    Hz), 4.01 (s, 1H), 3.22-3.17 (m, 2H), 2.98-2.95 (d, 1H, J=8.2 Hz),    2.91 (s, 3H), 2.67 (s, 1H), 1.92-1.86 (m, 2H), 1.60-1.50 (m, 2H),    1.45 (s, 6H); LCMS: Purity: 97%; MS (m/e): 521 (MH⁺);-   4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(4-(2-methylsulfonyl-2-azabicyclo[2.2.1]heptan-6-yl)phenyl)pyrimidin-2-amine,    compound #229, ¹H NMR (DMSO-d₆): δ 9.59 (s, 1H), 8.92 (s, 1H), 8.42    (d, 1H, J=5.0 Hz), 8.31 (d, 1H, J=9.1 Hz), 7.73 (d, 2H, J=8.5 Hz),    7.32 (d, 1H, J=5.0 Hz), 7.16 (d, 2H, J=8.5 Hz), 7.02 (d, 1H, J=9.1    Hz), 4.01 (s, 1H), 3.70-3.68 (m, 4H), 3.61-3.59 (m, 4H), 3.23-3.16    (m, 2H), 2.98-2.95 (d, 1H, J=8.2 Hz), 2.91 (s, 3H), 2.67 (s, 1H),    1.92-1.89 (m, 2H), 1.60-1.47 (m, 2H); LCMS: Purity: 87%; MS (m/e):    507 (MH⁺);-   4-(6-(thiamorpholin-4-yl)pyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #230, ¹H NMR (DMSO-d₆): δ 9.19 (s, 1H), 8.88 (s, 1H), 8.34    (d, 1H, J=5.3 Hz), 8.22 (d, 1H, J=8.8 Hz), 7.49 (d, 1H, J=8.8 Hz),    7.44 (s, 1H), 7.20 (d, 1H, J=5.3 Hz), 6.96 (d, 1H, J=9.1 Hz), 6.74    (d, 1H, J=9.1 Hz), 3.99 (s, 4H), 3.88 (s, 1H), 3.19 (d, 1H, J=9.1    Hz), 3.15 (d, 1H, J=9.1 Hz), 2.73 (d, 1H, J=9.1 Hz), 2.67 (d, 1H,    J=9.1 Hz), 2.61 (s, 4H), 2.26 (s, 3H), 2.18 (s, 3H), 1.77 (d, 1H,    J=9.1 Hz), 1.68 (d, 1H, J=9.1 Hz); LCMS: Purity: 99%; MS (m/e): 474    (MH⁺);-   4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine    as a hemi-succinate salt, compound #231;-   4-(1-(pyridin-4-yl)-1H-indol-5-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #232, ¹H NMR (DMSO-d₆, 300 MHz): δ 9.27 (s, 1H), 8.72 (m,    2H), 8.50 (s, 1H), 8.43 (d, 1H, J=5.4 Hz), 8.09 (d, 1H, J=8.7 Hz),    7.92 (m, 2H), 7.75 (dd, 2H, J=1.5 & 4.3 Hz), 7.51 (m, 2H), 7.35 (d,    1H, J=5.4 Hz), 6.92 (d, 1H, J=3.3 Hz), 6.76 (d, 1H, J=8.4 Hz), 3.90    (s, 1H), 3.19 (m, 3H), 2.72 (q, 2H, J=8.4 Hz), 2.28 (s, 3H), 2.22    (s, 3H), 1.79 (d, 1H, J=9.3 Hz), 1.70 (d, 1H, J=8.7 Hz); LCMS (m/z):    488 (MH⁺);-   4-(1-(pyridin-4-yl)-1H-indol-5-yl)-N-(3-fluoro-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #233, 1H NMR ((DMSO-d₆, 300 MHz): δ 9.48 (s, 1H), 8.71 (d,    1H, J=5.1 Hz), 8.49 (s, 1H), 8.46 (d, 1H, J=5.4 Hz), 8.25 (s, 1H),    8.09 (d, 1H, J=8.7 Hz), 7.92 (m, 2H), 7.74 (m, 2H), 7.39 (d, 2H,    J=4.8 Hz), 6.92 (d, 1H, J=3.3 Hz), 6.71 (t, 1H, J=9.9 Hz), 4.19 (s,    1H), 3.22 (m, 3H), 2.72 (q, 2H, J=8.4 Hz), 2.29 (s, 3H), 1.84 (d,    1H, J=9.6 Hz), 1.74 (d, 1H, J=9.3 Hz); LCMS (m/z): 492 (MH⁺);-   4-(1-(pyridin-4-yl)-1H-indol-5-yl)-N-(3-methyl-4-((1S,4S)-5-ethyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #234, ¹H NMR ((DMSO-d₆, 300 MHz): δ 9.28 (s, 1H), 8.72 (d,    2H, J=6.0 Hz), 8.50 (s, 1H), 8.42 (d, 1H, J=5.4 Hz), 8.09 (d, 1H,    J=9.0 Hz), 7.92 (m, 2H), 7.75 (d, 2H, J=6.0 Hz), 7.50 (m, 2H), 7.35    (d, 1H, J=5.4 Hz), 6.92 (d, 1H, J=3.6 Hz), 6.76 (d, 1H, J=8.7 Hz),    3.93 (s, 1H), 3.49 (s, 1H), 3.19 (s, 3H), 2.80 (m, 2H), 2.22 (s,    3H), 1.74 (m, 3H), 0.98 (t, 3H, J=7.2 Hz); LCMS (m/z): 502 (MH⁺);-   4-(1-(pyridin-4-yl)-1H-indol-5-yl)-N-(3-methyl-4-((1S,4S)-5-isobutyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #235, ¹H NMR ((DMSO-d₆, 300 MHz): δ 9.27 (s, 1H), 8.72 (m,    2H), 8.50 (s, 1H), 8.42 (d, 1H, J=5.4 Hz), 8.09 (d, 1H, J=8.7 Hz),    7.92 (m, 2H), 7.75 (dd, 2H, J=1.5 & 4.3 Hz), 7.51 (m, 2H), 7.35 (d,    1H, J=5.4 Hz), 6.92 (d, 1H, J=3.6 Hz), 6.74 (d, 1H, J=8.7 Hz), 3.91    (s, 1H), 3.39 (m, 1H), 3.20 (s, 2H), 2.81 (s, 1H)), 2.69 (s, 1H),    2.25 (s, 2H), 2.20 (s, 3H), 1.73 (m, 2H), 1.56 (s, 1H), 0.85 (d, 6H,    J=6.3 Hz); LCMS (m/z): 530 (MH⁺);-   4-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-methylsulfonyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #237, ¹H NMR (DMSO-d₆): δ 10.75 (1H, s), 9.38 (1H, s), 8.89    (1H, d, J=8.5 Hz), 8.45 (1H, d, J=5.2 Hz), 8.34-8.32 (m, 1H), 7.56    (1H, s), 7.48 (1H, d, J=8.5 Hz), 7.32 (1H, d, J=5.2 Hz), 6.89 (1H,    d, J=8.8 Hz), 4.35 (1H, s), 4.17 (1H, s), 3.07-2.97 (7H, m),    2.58-2.57 (4H, m), 2.23 (3H, s), 1.88 (2H, dd, J=25.2, 9.2 Hz); MS:    506 (M+H);-   4-(6-(propylamino)pyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-methylsulfonyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #238, ¹H NMR (DMSO-d₆): δ 9.23 (s, 1H), 8.77 (s, 1H), 8.33    (d, 1H, J=5.3 Hz), 8.11 (d, 1H, J=9.1 Hz), 7.53 (d, 1H, J=8.5 Hz),    7.48 (s, 1H), 7.31 (br s, 1H), 7.16 (d, 1H, J=5.3 Hz), 6.88 (d, 1H,    J=8.5 Hz), 6.60 (d, 1H, J=9.1 Hz), 4.33 (s, 1H), 4.14 (s, 1H),    3.41-3.22 (m, 6H), 2.95 (s, 3H), 2.19 (s, 3H), 1.90 (d, 1H, J=9.1    Hz), 1.88 (d, 1H, J=9.1 HZ), 1.55 (m, 2H), 0.90 (t, 3H, J=7.4 Hz);    LCMS: Purity: 99%; MS (m/e): 494 (MH⁺);-   4-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-7-yl)-N-(4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #239, ¹H NMR (CD₃OD, 300 MHz): δ 8.33 (m, 2H), 8.12 (s,    1H), 7.91 (m, 1H), 7.56 (m, 3H), 7.08 (m, 2H), 6.69 (m, 1H), 4.62    (s, 1H), 4.33 (s, 1H), 3.81 (m, 1H), 3.70 (m, 3H), 2.93 (s, 3H),    2.34 (m, 2H), 2.31 (m, 2H); MS (ES) 445.03 (M+H);-   4-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #240, ¹H NMR (CD₃OD, 300 MHz): δ 8.35 (m, 1H), 7.75 (m,    2H), 7.52 (m, 2H), 7.20 (m, 1H), 6.96 (m, 2H), 4.25 (m, 2H), 3.95    (m, 1H), 3.48 (m, 2H), 3.16 (m, 1H), 2.97 (s, 3H), 2.32 (m, 5H),    1.50 (s, 6H); MS (ES) 471.06 (M+H);-   4-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-N-(3-methyl-4-((1S,4S)-5-methylsulfonyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #241, ¹H NMR (CD₃OD, 300 MHz): δ 8.31 (m, 1H), 7.71 (m,    2H), 7.46 (m, 2H), 7.10 (m, 2H), 6.95 (m, 2H), 4.44 (s, 1H), 4.19    (s, 1H), 3.63-3.37 (m, 4H), 2.94 (s, 3H), 2.31 (s, 3H), 2.03 (m,    2H), 1.51 (s, 6H); MS (ES) 535.12 (M+H);-   4-(2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #242, ¹H NMR (CD₃OD, 300 MHz): δ 8.38 (m, 1H), 8.04 (m,    2H), 7.52 (m, 2H), 7.20 (m, 2H), 7.25 (m, 1H), 7.10 (m, 1H), 6.96    (m, 1H), 4.30 (s, 1H), 4.24 (s, 1H), 3.79 (m, 1H), 3.48 (m, 2H),    3.24 (m, 1H), 2.97 (s, 3H), 2.88 (m, 2H), 2.33 (m, 9H); MS (ES)    455.14 (M+H);-   4-(2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-yl)-N-(3-methyl-4-((1S,4S)-5-methylsulfonyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #243, ¹H NMR (CD₃OD, 300 MHz): δ 8.23 (m, 1H), 8.16 (m,    2H), 7.52 (m, 3H), 7.15 (m, 2H), 4.50 (s, 1H), 4.42 (s, 1H), 3.65    (m, 4H), 2.97 (s, 3H), 2.88 (m, 2H), 2.36-2.11 (m, 9H); MS (ES)    519.13 (M+H);-   4-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-N-(3-methyl-4-((6R,9S)-6,9-methanooctahydro-1H-pyrido[1,2-a]pyrazin-2-yl)phenyl)pyrimidin-2-amine,    compound #244, ¹H NMR (CD₃OD, 300 MHz): δ 8.42 (s, 1H), 8.36 (m,    1H), 7.76 (m, 2H), 7.55 (m, 2H), 7.21-7.10 (m, 2H), 6.97 (m, 1H),    3.95 (m, 2H), 3.70-3.48 (m, 3H), 2.58 (m, 1H), 2.41 (m, 1H), 1.34    (s, 3H), 1.97-1.66 (m, 6H), 1.51 (s, 6H); MS (ES) 511.13 (M+H);-   4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-methyl-4-((6R,9S)-6,9-methanooctahydro-1H-pyrido[1,2-a]pyrazin-2-yl)phenyl)pyrimidin-2-amine,    compound #245, ¹H NMR (CD₃OD, 300 MHz): δ 8.90 (m, 1H), 8.40 (s,    1H), 8.32-8.21 (m, 2H), 7.49 (m, 2H), 7.13 (m, 2H), 6.87 (m, 1H),    4.01-3.91 (m, 2H), 3.81-3.48 (m, 11H), 3.13 (m, 2H), 2.56 (m, 1H),    2.39 (m, 1H), 2.39 (m, 1H), 2.33 (s, 3H), 1.91-1.66 (m, 6H), 1.51    (s, 6H); MS (ES) 498.13 (M+H);-   4-(6-(dimethylamino)pyridin-3-yl)-N-(6-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)pyrimidin-2-amine,    compound #54, LCMS: purity: 99%; MS (m/e): 403 (MH⁺);-   4-(6-(methylcarbonylamino)pyridin-3-yl)-N-(6-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)pyrimidin-2-amine,    compound #55, LCMS: purity: 99%; MS (m/e): 417 (MH⁺);-   4-(4-(dimethylamino)phenyl)-N-(6-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)pyrimidin-2-amine,    compound #56, ¹H NMR (DMSO-d₆): δ 9.15 (s, 1H), 8.44 (s, 1H), 8.28    (d, 1H, J=6 Hz), 7.91 (m, 3H), 7.15 (d, 1H, J=5.6 Hz), 6.78 (d, 2H,    J=10 Hz), 6.57 (d, 1H, J=11.5 Hz), 4.65 (s, 1H), 3.51 (m, 2H), 2.98    (s, 6H), 2.69 (m, 2H), 2.57 (s, 3H), 2.08 (m, 1H), 1.93 (m, 1 Hz);    LCMS: purity: 99%; MS (m/e): 402 (MH⁺);-   4-(6-(4-acetylpiperazin-1-yl)pyridin-3-yl)-N-(6-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)pyrimidin-2-amine,    compound #57, ¹H NMR (DMSO-d₆): δ 9.21 (s, 1H), 8.88 (s, 1H), 8.41    (s, 1H), 8.34 (d, 1H, J=6 Hz), 8.20 (m, 1H), 7.83 (m, 1H), 7.22 (d,    1H, J=5.1 Hz), 6.95 (d, 1H, J=9.3 Hz), 6.53 (d, 1H, J=9.3 Hz), 4.60    (s, 1H), 3.59 (m, 12H), 2.92 (m, 1H), 2.44 (s, 3H), 2.01 (m, 4H),    1.79 (m, 1H); LCMS: purity: 99%; MS (m/e): 486 (MH⁺);-   4-(5-methyl-6-(morpholin-4-yl)pyridin-3-yl)-N-(6-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)pyrimidin-2-amine,    compound #58, LCMS: purity: 99%; MS (m/e): 459 (MH⁺);-   4-(6-(dimethylamino)pyridin-3-yl)-N-(5-methyl-6-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)pyrimidin-2-amine,    compound #61, LCMS: purity: 99%; MS (m/e): 417 (MH⁺);-   4-(4-(dimethylamino)phenyl)-N-(5-methyl-6-((1S,4S)-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)pyrimidin-2-amine,    compound #62, LCMS: purity: 99%; MS (m/e): 416 (MH⁺);-   4-(6-(4-acetylpiperazin-1-yl)pyridin-3-yl)-N-(5-methyl-6-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)pyrimidin-2-amine,    compound #63, LCMS: purity: 99%; MS (m/e): 500 (MH⁺);-   4-(5-methyl-6-(morpholin-4-yl)pyridin-3-yl)-N-(5-methyl-6-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)pyrimidin-2-amine,    compound #64, LCMS: purity: 99%; MS (m/e): 473 (MH⁺);-   4-(4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(5-methyl-6-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)pyrimidin-2-amine,    compound #65, LCMS: purity: 99%; MS (m/e): 445 (MH⁺);-   4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(5-methyl-6-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)pyrimidin-2-amine,    compound #66, LCMS: purity: 99%; MS (m/e): 459 (MH⁺);-   4-(4-(t-butylcarbonylamino)phenyl)-N-(5-methyl-6-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)pyrimidin-2-amine,    compound #131, ¹H NMR (CD₃OD, 300 MHz): δ 9.26 (m, 1H), 8.64 (m,    1H), 8.41 (m, 1H), 8.11 (m, 2H), 7.90 (m, 1H), 7.74 (m, 2H), 7.37    (m, 1H), 4.29 (s, 1H), 4.40 (m, 2H), 3.99 (m, 2H), 3.36 (m, 1H),    3.24 (m, 1H), 3.01 (s, 3H), 2.40 (m, 5H), 1.33 (s, 9H); MS (ES)    472.12 (M+H);-   4-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(5-methyl-6-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)pyrimidin-2-amine,    compound #138, ¹H NMR (CD₃OD, 300 MHz): δ 8.69 (m, 1H), 8.56 (m,    1H), 8.45 (m, 1H), 8.00 (m, 2H), 7.90 (m, 1H), 7.31 (m, 1H), 4.78    (m, 1H), 4.38 (s, 1H), (m, 1H), 4.08 (m, 1H), 3.96 (m, 1H), 3.63 (m,    1H), 3.23 (m, 1H), 3.00 (s, 3H), 2.38 (m, 5H), 1.54 (s, 6H); MS (ES)    473.10 (M+H);-   4-(4-(3-cyclopropylureido)phenyl)-N-(5-methyl-6-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)pyrimidin-2-amine,    compound #140, ¹H NMR (CD₃OD, 300 MHz): δ 8.46 (m, 1H), 8.33 (m,    1H), 8.15 (m, 1H), 8.03 (m, 2H), 7.85 (m, 1H), 7.53 (m, 2H), 7.20    (m, 1H), 4.65 (s, 1H), 4.31 (s, 1H), 3.92 (m, 2H), 3.58 (m, 1H),    2.96 (s, 3H), 2.61 (m, 1H), 2.30 (m, 5H), 0.76 (m, 2H), 0.53 (m,    3H); MS (ES) 471.57 (M+H);-   4-(6-(2-(morpholin-4-yl)acetamido)pyridin-3-yl)-N-(5-methyl-6-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)pyrimidin-2-amine,    compound #144, ¹H NMR (CD₃OD, 300 MHz): δ 9.10 (m, 1H), 8.53 (m,    3H), 8.25 (m, 1H), 7.87 (m, 1H), 7.33 (m, 1H), 4.23 (m, 4H), 3.98    (m, 4H), 3.46 (m, 4H), 3.34 (m, 1H), 3.23 (m, 1H), 2.99 (s, 3H),    2.35 (m, 6H); MS (ES) 516.07 (M+H);-   4-(6-aminopyridin-3-yl)-N-(5-methyl-6-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)pyrimidin-2-amine,    compound #145, ¹H NMR (CD₃OD, 300 MHz): δ 8.70 (m, 1H), 8.39 (m,    1H), 8.33 (m, 1H), 8.20 (m, 3H), 7.84 (m, 1H), 7.14 (m, 1H), 6.66    (m, 1H), 4.64 (s, 1H), 4.30 (s, 1H), 3.99 (m, 1H), 3.86 (m, 1H),    3.58 (m, 1H), 2.96 (s, 3H), 2.65 (m, 1H), 2.30 (m, 5H); MS (ES)    389.01 (M+H);-   4-(6-(acetamido)pyridin-3-yl)-N-(5-methyl-6-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)pyrimidin-2-amine,    compound #146, ¹H NMR (CD₃OD, 300 MHz): δ 9.02 (m, 1H), 8.44 (m,    2H), 8.23 (m, 2H), 7.83 (m, 1H), 7.25 (m, 1H), 4.65 (s, 1H), 4.30    (s, 1H), 4.00 (m, 1H), 3.85 (m, 1H), 3.59 (m, 2H), 2.96 (s, 3H),    2.65 (m, 1H), 2.30 (s, 3H), 2.21 (m, 2H); MS (ES) 431.05 (M+H);-   4-(6-(methylsulfonylamino)pyridin-3-yl)-N-(5-methyl-6-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)pyrimidin-2-amine,    compound #154, ¹H NMR (CD₃OD, 300 MHz): δ 8.96 (m, 1H), 8.41 (m,    2H), 8.20 (m, 2H), 7.83 (m, 1H), 7.20 (m, 2H), 4.65 (s, 1H), 4.30    (s, 1H), 4.02-3.57 (m, 3H), 2.97 (s, 3H), 2.30 (m, 6H); MS (ES)    467.02 (M+H);-   4-(2-(dimethylamino)thiazol-4-yl)-N-(6-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)pyrimidin-2-amine,    compound #177, ¹H NMR (DMSO-d₆): δ 9.20 (s, 1H), 8.41 (d, 1H, J=4.7    Hz), 8.33 (s, 1H), 7.86 (d, 1H, J=8.5 Hz), 7.47 (s, 1H), 7.18 (d,    1H, J=4.7 Hz), 6.47 (d, 1H, J=9.1 Hz), 4.48 (s, 1H), 3.40-3.37 (m,    2H), 3.23 (d, 1H, J=9.7 Hz), 3.07 (s, 6H), 2.77 (d, 1H, J=9.1 Hz),    2.42 (d, 1H, J=9.7 Hz), 2.24 (s, 3H), 1.83 (d, 1H, J=9.1 Hz), 1.70    (d, 1H, J=9.1 Hz); LCMS: purity: 99%; MS (m/e): 409 (MH⁺);-   4-(5-(morpholin-4-yl)pyrazin-2-yl)-N-(6-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)pyrimidin-2-amine,    compound #180, ¹H NMR (DMSO-d₆): δ 9.25 (s, 1H), 8.94 (s, 1H),    8.42-8.36 (m, 3H), 7.83 (dd, 1H, J=2.0 and 9.1 Hz), 7.35 (d, 1H,    J=4.9 Hz), 6.51 (d, 1H, J=9.1 Hz), 4.50 (s, 1H), 3.69-3.67 (m, 8H),    3.41-3.38 (m, 2H), 3.23 (d, 1H, J=9.4 Hz), 2.77 (d, 1H, J=9.4 Hz),    2.43 (d, 1H, J=9.4 Hz), 2.23 (s, 3H), 1.83 (d, 1H, J=9.7 Hz), 1.71    (d, 1H, J=9.7 Hz); LCMS: purity: 90%; MS (m/e): 446 (MH⁺);-   4-(1-(pyridin-4-yl)-1H-indol-5-yl)-N-(5-methyl-6-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)pyrimidin-2-amine,    compound #236, ¹H NMR ((DMSO-d₆, 300 MHz): δ 9.33 (s, 1H), 8.72 (d,    2H, J=6.3 Hz), 8.50 (s, 1H), 8.48 (s, 1H), 8.43 (d, 1H, J=5.1 Hz),    8.32 (s, 1H), 8.07 (d, 1H, J=9.0 Hz), 7.92 (m, 2H), 7.79 (s, 1H),    7.75 (d, 2H, J=6.3 Hz), 7.38 (d, 1H, J=5.4 Hz), 6.91 (d, 1H, J=3.6    Hz), 4.36 (s, 1H), 3.38 (m, 2H), 2.79 (m, 2H), 2.27 (s, 3H), 2.23    (s, 3H), 1.77 (d, 1H, J=8.7 Hz), 1.64 (d, 1H, J=9.0 Hz); LCMS (m/z):    489 (MH⁺);-   4-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(3-methyl-4-((1S,4S)-5-(1-methylethyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #246, ¹H NMR (DMSO-d₆, 300 MHz): δ 11.48 (b, 1H), 9.44 (d,    J=4.96 Hz, 1H), 8.73 (b, 1H), 8.46 (d, J=4.95 Hz, 1H), 8.02 (b, 1H),    7.57 (tr, J=19.53 Hz, 2H), 7.37 (d, J=4.40 Hz, 1H), 6.94 (m, 1H),    2.25-2.08 (m, 8H), 1.47 (s, 6H), 1.36-1.23 (m, 9H); LCMS: purity;    95%; [M+H]=500;-   4-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(3-methyl-4-((1S,4S)-5-cyclopropyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #247, ¹H NMR (DMSO-d₆, 300 MHz): δ 11.48 (b, 1H), 9.44 (d,    J=4.96 Hz, 1H), 8.73 (b, 1H), 8.46 (d, J=4.95 Hz, 1H), 8.02 (b, 1H),    7.57 (tr, J=19.53 Hz, 2H), 7.37 (d, J=4.40 Hz 1H), 6.94 (m, 1H), 2.5    (b, 8H), 2.21 (b, 3H), 1.86 (b, 1H), 1.47 (s, 6H), 0.91-0.87 (b,    4H); LCMS: purity; 100%; [M+H]⁺=498;-   4-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(3-chloro-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #248, ¹H NMR (CD₃OD, 300 MHz): δ 8.68 (s, 1H), 8.42 (m,    1H), 8.31 (s, 1H), 7.98 (m, 2H), 7.53 (m, 1H), 7.27 (m, 1H), 7.08    (m, 1H), 4.40 (m, 2H), 3.81 (m, 2H), 3.61 (m, 1H), 2.97 (s, 3H),    2.66 (m, 4H), 2.29 (m, 2H), 1.55 (s, 6H); LCMS (m/z): 492.09 (MH⁺);-   4-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(3-chloro-4-((1S,4S)-5-(methylsulfonyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #249, LCMS (m/z): 556.00 (ELSD);-   4-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(3-methyl-4-((1S,4S)-5-cyclopentyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #250, ¹H NMR (CD₃OD, 300 MHz): δ 8.44 (m, 2H), 8.09 (m,    1H), 8.00 (m, 1H), 7.77 (m, 1H), 7.27 (m, 1H), 6.95 (m, 1H), 4.78    (m, 1H), 4.50 (m, 1H), 4.05 (m, 1H), 3.71 (m, 3H), 3.51 (m, 1H),    2.31 (s, 3H), 2.27 (m, 4H), 1.74 (m, 4H), 1.54 (s, 6H) ppm; MS (ES)    526.2 (M+H);-   4-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(3-methyl-4-((1S,4S)-5-acetyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #251, ¹H NMR (CD₃OD, 300 MHz): δ 8.67 (m, 1H), 8.42 (m,    1H), 8.00 (m, 2H), 7.71 (m, 1H), 7.24 (m, 1H), 6.88 (m, 1H), 3.63    (m, 3H), 3.38 (m, 3H), 2.15 (s, 3H), 2.01 (m, 2H), 1.54 (s, 6H) ppm;    MS (ES) 500.2 (M+H);-   4-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(3-methyl-4-(1,4-diazabicyclo[3.2.1]octan-4-yl)phenyl)pyrimidin-2-amine,    compound #252, ¹H NMR (CD₃OD, 300 MHz): δ 8.71 (m, 1H), 8.41 (m,    1H), 7.59 (m, 2H), 7.25 (m, 2H), 7.12 (m, 1H), 3.91 (m, 1H), 3.57    (m, 5H), 3.27 (m, 2H), 3.07 (m, 1H), 2.36 (s, 3H), 2.13 (m, 2H),    1.54 (s, 6H) ppm; MS (ES) 472.1 (M+H);-   4-(5-(1-methylethoxy)carbonylpropyl-6-aminopyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #253, ¹H NMR (DMSO-d₆, 300 MHz): δ 9.16 (s, 1H), 8.62 (b,    1H), 8.30 (d, J=5.23 Hz, 1H), 7.94 (b, 1H), 7.53 (b, 1H), 7.43 (d,    J=8.53 Hz, 1H), 7.16 (d, J=5.22 Hz, 1H), 6.78 (d, J=8.52 Hz, 1H),    6.37 (b, 2H), 4.88-4.84 (m, 1H), 2.82 (b, 1H), 2.49-2.48 (m, 5H),    2.39-2.30 (m, 3H), 2.20 (s, 3H), 1.85-1.76 (m, 5H), 1.16 (d, J=6.5    Hz, 9H); LCMS: purity; 96.5%; [M+H]⁺=516;-   4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-cyclopropyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine;    compound #254, ¹H NMR (DMSO-d₆, 300 MHz): δ 9.18 (s, 1H), 8.90 (b,    1H), 8.35 (d, J=5.22 Hz, 1H), 8.26 (d, J=9.08 Hz, 1H), 7.48 (b, 2H),    7.21 (d, J=5.23 Hz, 1H), 6.96 (d, J=9.36 Hz, 1H), 6.76 (d, J=8.80    Hz, 1H), 3.93 (b, 1H), 3.70 (d, J=4.4 Hz, 4H), 3.59 (d, J=4.67 Hz,    4H) 2.87 (b, 2H), 2.49 (b, 3H), 2.20 (s, 3H), 1.95 (b, 1H), 1.74 (d,    J=4.68 Hz, 2H), 0.37 (d, J=23.39 Hz, 4H); LCMS: purity; 97%;    [M+H]⁺=484;-   4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-chloro-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #255, ¹H NMR (CD₃OD, 300 MHz): δ 8.94 (s, 1H), 8.34 (m,    1H), 8.32 (s, 1H), 8.22 (m, 1H), 7.82 (m, 1H), 7.53 (M, 1H), 7.19    (m, 1H), 7.08 (m, 1H), 6.82 (m, 1H), 4.36 (m, 2H), 3.79 (m, 6H),    3.61 (m, 6H), 2.97 (s, 3H), 2.29 (m, 2H); LCMS (m/z): 478.05 (MH⁺);-   4-(2-(trifluoromethyl)pyridin-4-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #256, LCMS (m/z): 441.05 (MH⁺);-   4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-chloro-4-((1S,4S)-5-(methylsulfonyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #257, LCMS (m/z): 541.00 (ELSD);-   4-(6-(tetrahydropyran-4-yloxy)pyridin-3-yl)-N-(3-chloro-4-((1S,4S)-5-(methylsulfonyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #258, LCMS (m/z): 557.02 (MH⁺);-   4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-chloro-4-((1S,4S)-5-acetyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #259, LCMS (m/z): 506.01 (MH⁺);-   4-(6-(tetrahydropyran-4-yloxy)pyridin-3-yl)-N-(3-chloro-4-((1S,4S)-5-acetyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #260, LCMS (m/z): 521.08 (MH⁺);-   4-(6-(tetrahydropyran-4-yloxy)pyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #261, ¹H NMR (CD₃OD, 300 MHz): δ 8.89 (m, 1H), 8.36 (m,    2H), 7.55 (m, 1H), 7.45 (m, 1H), 7.18 (m, 1H), 6.99 (m, 1H), 6.88    (m, 1H), 5.28 (m, 1H), 4.25 (m, 2H), 3.94 (m, 2H), 3.76 (m, 1H),    3.55 (m, 5H), 2.97 (s, 3H), 2.30 (s, 3H), 2.06 (m, 3H), 1.76 (m, 3H)    ppm; MS (ES) 473.2 (M+H);-   4-(6-(tetrahydropyran-4-yloxy)pyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-cyclopentyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #262, ¹H NMR (CD₃OD, 300 MHz): δ 8.88 (m, 1H), 8.42 (m,    1H), 8.34 (m, 1H), 8.05 (m, 1H), 7.79 (m, 1H), 7.23 (m, 1H), 6.94    (m, 1H), 6.86 (m, 1H), 5.29 (m, 1H), 4.00 (m, 4H), 3.62 (m, 7H),    2.32 (m, 7H), 1.75 (m, 10H) ppm; MS (ES) 527.2 (M+H);-   4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-chloro-4-((1S,4S)-5-(1-methylethyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #263, ¹H NMR (DMSO-d₆, 300 MHz): δ 9.18 (s, 1H), 8.90 (b,    1H), 8.35 (d, J=5.22 Hz, 1H), 8.26 (d, J=9.08 Hz, 1H), 7.48 (b, 2H),    7.21 (d, J=5.23 Hz, 1H), 6.96 (d, J=9.36 Hz, 1H), 6.76 (d, J=8.80    Hz, 1H), 3.93 (b, 1H), 3.70 (d, J=4.4 Hz, 4H), 3.59 (d, J=4.67 Hz,    4H), 3.23-2.96 (m, 3H), 2.49 (b, 3H), 2.20 (s, 3H), 1.72 (b, 2H),    0.97 (d, J=4.13 Hz, 6H); LCMS: purity; 99.7%; [M+H]⁺=486;    4-(6-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)pyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-(methylsulfonyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #264, ¹H NMR (DMSO-d₆): δ 9.30 (s, 1H), 8.84 (s, 1H), 8.35    (d, 1H, J=5.0 Hz), 8.25 (d, 1H, J=7.3 Hz), 7.53 (d, 1H, J=8.8 Hz),    7.47 (s, 1H), 7.22 (d, 1H, J=5.0 Hz), 6.88 (d, 1H, J=8.5 Hz), 6.72    (d, 1H, J=7.3 Hz), 4.98 (s, 1H), 4.69 (s, 1H), 4.33 (s, 1H), 4.15    (s, 1H), 3.79 (d, 1H, J=6.7 Hz), 3.66 (d, 1H, J=6.7 hz), 3.53-3.39    (m, 6H), 2.95 (s, 3H), 2.20 (s, 3H), 1.95-1.80 (m, 4H). LCMS:    Purity: 99%; MS (m/e): 534 (MH⁺);-   4-(6-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)pyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #265, ¹H NMR (DMSO-d₆): δ 9.27 (s, 1H), 8.87 (d, 1H, J=2.3    Hz), 8.33 (d, 1H, J=5.3 Hz), 8.21 (dd, 1H, J=2.0 and 8.8 Hz), 7.56    (d, 1H, 9.1 Hz), 7.48 (d, 1H, J=5.3 Hz), 7.20 (d, 1H, J=5.3 Hz),    6.86 (d, 1H, J=8.8 Hz), 6.64 (d, 1H, J=8.8 Hz), 4.96 (s, 1H), 4.68    (s, 1H), 3.79 (d, 1H, J=6.7 Hz), 3.65 (d, 1H, J=7.6 Hz), 3.5 (d, 1H,    J=10.2 Hz), 3.16 (m, 2H), 2.75 (d, 1H, J=9.3 Hz), 2.67 (d, 1H, J=9.3    Hz), 2.29 (s, 3H), 2.20 (s, 3H), 1.90 (m, 4H); LCMS: purity: 99%; MS    (m/e): 470 (MH⁺);-   4-(6-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)pyridin-3-yl)-N-(5-methyl-6-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)pyrimidin-2-amine,    compound #266, ¹H NMR (DMSO-d₆): δ 9.22 (s, 1H), 8.85 (s, 1H),    8.34-8.33 (m, 2H), 8.18 (d, 1H, J=6.7 Hz), 7.70 (s, 1H), 7.20 (d,    1H, J=5.3 Hz), 6.65 (d, 1H, J=8.8 Hz), 4.96 (s, 1H), 4.67 (s, 1H),    4.34 (s, 1H), 3.78 (d, 1H, J=7.0 Hz), 3.64 (d, 1H, J=7.0 Hz), 3.49    (d, 1H, J=9.5 Hz), 3.42-3.36 (m, 4H), 2.74 (s, 2H), 2.24 (s, 3H),    2.19 (s, 3H), 1.92 (d, 1H, J=9.1 Hz), 1.85 (d, 1H, J=9.1 Hz), 1.74    (d, 1H, J=9.1 Hz), 1.62 (d, 1H, J=9.1 Hz). LCMS: Purity: 99%; MS    (m/e): 471 (MH+);-   4-(6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-3-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #267, ¹H NMR (DMSO-d₆, 300 MHz): δ 9.24 (b, 1H), 8.47 (d,    J=5.50 Hz, 1H), 8.20 (b, 1H), 7.88 (d, J=7.16 Hz, 1H), 7.55 (d,    J=5.50 Hz, 1H), 7.38 (b, 1H), 7.24-7.17 (m, 2H), 6.74 (d, J=8.52 Hz,    1H), 3.91 (b, 1H), 3.20 (b, 4H), 3.05 (b, 3H), 8.30 (m, 3H), 2.32    (s, 3H), 2.18 (s, 3H), 1.81-1.71 (m, 5H); LCMS: purity; 98.1%;    [M+H]⁺=466;-   4-(6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-3-yl)-N-(3-methyl-4-((1S,4S)-5-(methylsulfonyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #268, ¹H NMR (DMSO-d₆, 300 MHz): δ 9.24 (b, 1H), 8.47 (d,    J=5.50 Hz, 1H), 8.20 (b, 1H), 7.88 (d, J=7.16 Hz, 1H), 7.55 (d,    J=5.50 Hz, 1H), 7.38 (b, 1H), 7.29-7.17 (m, 2H), 6.86 (b, 1H), 4.34    (b, 1H), 4.17 (b, 2H), 3.37-3.25 (m, 5H), 3.04 (b, 1H), 2.96 (s,    3H), 2.67 (b, 2H), 2.20 (b, 3H), 1.89-1.81 (m, 5H); LCMS: purity;    98.7%; [M+H]⁺=530;-   4-(4-(trifluoromethyl)phenyl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #269, LCMS (m/z): 440.09 (MH⁺);-   4-(7,8,9,9a-tetrahydro-5H-pyrido[2,3-e]pyrrolo[1,2-a][1,4]diazepin-10(11H)-on-3-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #270, ¹H NMR (CD₃OD, 300 MHz): δ 9.28 (m, 1H), 8.63 (m,    1H), 8.43 (m, 1H), 7.42 (m, 3H), 7.01 (m, 1H), 4.78 (m, 2H), 4.55    (m, 1H), 4.41 (m, 2H), 4.30 (s, 1H), 3.99 (m, 3H), 3.50-3.36 (m,    3H), 3.16 (m, 1H), 2.99 (s, 3H), 2.82 (m, 1H), 2.32 (m, 5H), 2.10    (m, 3H); MS (ES) 497.10 (M+H);-   4-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-N-(3-cyano-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #271, ¹H NMR (CD₃OD, 300 MHz): δ 8.39 (m, 2H), 8.16 (m,    1H), 7.72 (m, 3H), 7.20 (m, 1H), 6.94 (m, 2H), 4.76 (s, 1H), 4.32    (s, 1H), 4.04 (m, 1H), 3.69 (m, 2H), 3.31 (m, 2H), 2.93 (s, 3H),    2.35 (m, 2H), 1.51 (s, 6H); MS (ES) 482.08 (M+H);-   4-(2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-yl)-N-(3-cyano-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #272, ¹H NMR (CD₃OD, 300 MHz): δ 8.41 (m, 3H), 8.08 (s,    1H), 7.99 (m, 1H), 7.66 (m, 1H), 7.28 (m, 1H), 7.11 (m, 1H), 6.93    (m, 1H), 4.77 (s, 1H), 4.34 (s, 1H), 4.07 (m, 1H), 3.69 (m, 2H),    3.35 (m, 2H), 2.95 (s, 3H), 2.89 (m, 2H), 2.32 (m, 6H); MS (ES)    466.08 (M+H);-   4-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-7-yl)-N-(3-cyano-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #273, ¹H NMR (CD₃OD, 300 MHz): δ 8.39 (m, 2H), 8.12 (s,    1H), 7.93 (m, 1H), 7.71 (m, 1H), 7.23 (m, 1H), 7.05 (m, 1H), 6.92    (m, 1H), 4.77 (s, 1H), 4.30 (s, 1H), 4.07 (m, 1H), 3.69 (m, 2H),    3.48 (s, 2H), 3.30 (m, 3H), 2.93 (s, 3H), 2.33 (m, 2H); MS (ES)    470.06 (M+H);-   4-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-7-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,    compound #274, ¹H NMR (CD₃OD, 300 MHz): δ 8.36 (m, 2H), 8.17 (s,    1H), 7.91 (m, 1H), 7.48 (m, 2H), 7.19 (m, 1H), 7.04 (m, 1H), 6.96    (m, 1H), 4.29 (s, 1H), 4.24 (s, 1H), 3.81 (m, 1H), 3.52 (m, 4H),    2.97 (s, 3H), 2.33 (s, 3H), 2.31 (s, 2H); MS (ES) 459.07 (M+H);-   4-(6-(tetrahydropyran-4-yloxy)pyridin-3-yl)-N-(3-methyl-4-(1,4-diazabicyclo[3.2.1]octan-4-yl)phenyl)pyrimidin-2-amine,    compound #275, ¹H NMR (CD₃OD, 300 MHz): δ 8.92 (m, 1H), 8.38 (m,    2H), 7.62 (m, 1H), 7.53 (m, 1H), 7.21 (m, 1H), 7.11 (m, 1H), 6.88    (m, 1H), 5.30 (m, 1H), 3.95 (m, 4H), 3.58 (m, 8H), 3.11 (m, 1H),    2.35 (s, 3H), 2.12 (m, 4H), 1.78 (m, 3H) ppm; MS (ES) 473.2 (M+H);-   4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-methyl-4-((R)-1,4-diazabicyclo[3.2.1]octan-4-yl)phenyl)pyrimidin-2-amine,    compound #276, ¹H NMR (CD₃OD, 300 MHz): δ 8.92 (m, 1H), 8.32 (m,    1H), 8.24 (m, 1H), 7.59 (m, 1H), 7.55 (m, 1H), 7.13 (m, 2H), 6.86    (m, 1H), 3.92 (m, 1H), 3.79 (m, 4H), 3.61 (m, 9H), 3.31 (m, 1H),    3.10 (m, 2H), 2.35 (s, 3H), 2.13 (m, 2H) ppm; MS (ES) 458.1 (M+H);-   4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-methyl-4-((S)-1,4-diazabicyclo[3.2.1]octan-4-yl)phenyl)pyrimidin-2-amine,    compound #277, ¹H NMR (CD₃OD, 300 MHz): δ 8.92 (m, 1H), 8.31 (m,    1H), 8.25 (m, 1H), 7.58 (m, 2H), 7.14 (m, 2H), 6.88 (m, 1H), 3.93    (m, 1H), 3.77 (m, 4H), 3.59 (m, 9H), 3.32 (m, 1H), 3.11 (m, 2H),    2.36 (s, 3H), 2.14 (m, 2H) ppm; MS (ES) 458.1 (M+H);-   4-(2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-yl)-N-(3-methyl-4-((6R,9S)-6,9-methanooctahydro-1H-pyrido[1,2-a]pyrazin-2-yl)phenyl)pyrimidin-2-amine,    compound #278, ¹H NMR (CD₃OD, 300 MHz): δ 8.37 (m, 2H), 8.05 (m,    2H), 7.58 (m, 1H), 7.25 (m, 1H), 7.10 (m, 2H), 4.01 (m, 3H), 3.55    (m, 5H), 3.14 (m, 2H), 2.88 (m, 2H), 2.57 (m, 1H), 2.34 (m, 7H),    1.80 (m, 6H); MS (ES) 495.14 (M+H);-   4-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-7-yl)-N-(3-methyl-4-((6R,9S)-6,9-methanooctahydro-1H-pyrido[1,2-a]pyrazin-2-yl)phenyl)pyrimidin-2-amine,    compound #279, ¹H NMR (CD₃OD, 300 MHz): δ 8.34 (m, 1H), 8.21 (s,    1H), 7.98 (m, 1H), 7.53 (m, 2H), 7.32 (m, 1H), 7.08 (m, 2H), 4.03    (s, 1H), 3.96 (m, 2H), 3.63 (m, 5H), 3.12 (m, 3H), 2.59 (s, 2H),    2.37 (s, 3H), 1.92-1.63 (m, 6H); MS (ES) 499.04 (M+H);-   4-(6-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)pyridin-3-yl)-N-(3-methyl-4-(1,4-diazabicyclo[3.2.2]nonan-4-yl)phenyl)pyrimidin-2-amine,    compound #280, ¹H NMR (CD₃OD, 300 MHz): δ 8.88 (m, 1H), 8.32 (m,    3H), 7.52 (m, 2H), 7.22 (m, 2H), 6.63 (m, 1H), 4.74 (s, 1H),    3.92-3.81 (m, 2H), 3.58 (m, 4H), 3.43 (m, 4H), 2.65 (m, 2H), 2.43    (m, 2H), 2.36 (s, 3H), 2.13-2.03 (m, 4H); MS (ES) 484.16 (M+H);-   4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-cyano-4-(3,9-diazabicyclo[3.3.2]decan-10-on-3-yl)phenyl)pyrimidin-2-amine,    compound #281, ¹H NMR (CD₃OD, 300 MHz): δ 8.88 (s, 1H), 8.37 (d,    1H), 8.25 (m, 1H), 8.17 (d, 1H), 7.82 (m, 1H), 7.24 (m, 2H), 6.87    (d, 1H), 3.80 (m, 4H), 3.62 (m, 4H), 3.41 (m, 2H), 3.14 (m, 2H),    2.85 (m, 1H), 2.25 (m, 4H), 2.01 (m, 2H), 1.55 (m, 1H); LCMS (m/z):    510.00 (ELSD);-   4-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-(3-cyano-4-(3,9-diazabicyclo[3.3.2]decan-10-on-3-yl)phenyl)pyrimidin-2-amine,    compound #282, ¹H NMR (DMSO, 300 MHz): δ 11.5 (s, 1H), 9.87 (s, 1H),    8.73 (s, 1H), 8.54 (d, 1H), 8.24 (s, 1H), 8.03 (d, 1H), 7.84 (m,    2H), 7.46 (d, 1H), 7.31 (d, 1H), 3.41 (m, 1H), 3.11 (m, 1H), 3.02    (m, 2H), 2.68 (m, 1H), 2.11 (m, 4H), 1.83 (m, 1H), 1.46 (s, 6H);    LCMS (m/z): 525.01 (MH⁺);-   4-(6-(tetrahydropyran-4-yloxy)pyridin-3-yl)-N-(3-methyl-4-(3-(dimethylamino)-8-azabicyclo[3.2.1]octan-8-yl)phenyl)pyrimidin-2-amine,    compound #283, ¹H NMR (CD₃OD, 300 MHz): δ 8.90 (m, 1H), 8.36 (m,    2H), 7.46 (m, 2H), 7.17 (m, 1H), 6.86 (m, 2H), 5.28 (m, 1H), 3.94    (m, 4H), 3.60 (m, 3H), 2.86 (s, 6H), 2.37 (s, 3H), 2.02 (m, 9H),    1.79 (m, 3H) ppm; MS (ES) 515.2 (M+H);-   4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-methyl-4-(3-(morpholin-4-yl)-8-azabicyclo[3.2.1]octan-8-yl)phenyl)pyrimidin-2-amine,    compound #284, ¹H NMR (CD₃OD, 300 MHz): δ 8.92 (m, 1H), 8.26 (m,    2H), 7.46 (m, 2H), 7.12 (m, 1H), 6.87 (m, 2H), 3.82 (m, 11H), 3.55    (m, 6H), 2.37 (s, 3H), 2.06 (m, 8H), 1.78 (m, 2H) ppm; MS (ES) 542.3    (M+H);-   4-(6-(tetrahydropyran-4-yloxy)pyridin-3-yl)-N-(3-methyl-4-(3-(morpholin-4-yl)-8-azabicyclo[3.2.1]octan-8-yl)phenyl)pyrimidin-2-amine,    compound #285, ¹H NMR (CD₃OD, 300 MHz): δ 8.93 (m, 1H), 8.25 (m,    2H), 7.47 (m, 2H), 7.13 (m, 1H), 6.88 (m, 2H), 5.28 (m, 1H), 3.84    (m, 11H), 3.54 (m, 6H), 2.37 (s, 3H), 2.08 (m, 8H), 1.79 (m, 2H)    ppm; MS (ES) 557.3 (M+H); and-   4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-methyl-4-(3-(dimethylamino)-8-azabicyclo[3.2.1]octan-8-yl)phenyl)pyrimidin-2-amine,    compound #286, ¹H NMR (CD₃OD, 300 MHz): δ 8.89 (m, 1H), 8.27 (m,    1H), 8.21 (m, 1H), 7.45 (m, 2H), 7.08 (m, 1H), 6.84 (m, 2H), 3.87    (m, 2H), 3.77 (m, 2H), 3.54 (m, 3H), 2.84 (s, 6H), 2.37 (s, 3H),    2.02 (m, 9H), 1.77 (m, 3H) ppm; MS (ES) 500.3 (M+H).    Testing of the Compounds of the Invention

Exemplary compounds of the invention were tested in the followingbiological assays for their ability to inhibit JAK activity.

Biological Example 1 Assay for Ramos B-Cell Line Stimulated with IL-4

B-cells stimulated with cytokine Interleukin-4 (IL-4) activate theJAK/Stat pathway through phosphorylation of the JAK family kinases,JAK-1 and JAK-3, which in turn phosphorylate and activate thetranscription factor Stat-6. One of the genes upregulated by activatedStat-6 is the low affinity IgE receptor, CD23. To study the effect ofinhibitors on the JAK family kinases, human Ramos B cells are stimulatedwith human IL-4.

The Ramos B-cell line was acquired from ATCC (ATCC Catalog No.CRL-1596). The cells were cultured in RPMI 1640 (Cellgro, MediaTech,Inc., Herndon, Va., Cat No. 10-040-CM) with 10% fetal bovine serum(FBS), heat inactivated (JRH Biosciences, Inc, Lenexa, Kans., Cat No.12106-500M) according to ATCC propagation protocol. Cells weremaintained at a density of 3.5×10⁵. The day before the experiment, RamosB-cells were diluted to 3.5×10⁵ cells/mL to ensure that they were in alogarithmic growth phase.

Cells were spun down and suspended in RPMI with 5% serum. 5×10⁴ cellswere used per point in a 96-well tissue culture plate. Cells werepre-incubated with compound or DMSO (Sigma-Aldrich, St. Louis, Mo., CatNo. D2650) vehicle control for 1 hour in a 37° C. incubator.

Cells were then stimulated with IL-4 (Peprotech Inc., Rocky Hill, N.J.,Cat No. 200-04) for a final concentration of 50 units/mL for 20-24hours. Cells were then spun down and stained with anti-CD23-PE(BDPharmingen, San Diego, Calif., Cat No. 555711) and analyzed by FACS(Fluorescence Activated Cell Sorting). Detection was performed using aBD LSR I System Flow Cytometer, purchased from Becton DickinsonBiosciences of San Jose, Calif.

Biological Example 2 Primary Human T-Cell Proliferation Assay Stimulatedwith IL-2

Primary human T-cells derived from peripheral blood and pre-activatedthrough stimulation of the T-cell receptor and CD28, proliferate invitro in response to the cytokine Interleukin-2 (IL-2). Thisproliferative response is dependent on the activation of JAK-1 and JAK-3tyrosine kinases, which phosphorylate and activate the transcriptionfactor Stat-5.

Human primary T cells were prepared as follows. Whole blood was obtainedfrom a healthy volunteer, mixed 1:1 with PBS, layered on to FicollHypaque (Amersham Pharmacia Biotech, Piscataway, N.J., Catalog#17-1440-03) in 2:1 blood/PBS:ficoll ratio and centrifuged for 30 min at4° C. at 1750 rpm. The lymphocytes at the serum:ficoll interface wererecovered and washed twice with 5 volumes of PBS. The cells wereresuspended in Yssel's medium (Gemini Bio-products, Woodland, Calif.,Catalog #400-103) containing 40 U/mL recombinant IL2 (R and D Systems,Minneapolis, Minn., Catalog #202-IL (20 μg)) and seeded into a flaskpre-coated with 1 μg/mL anti-CD3 (BD Pharmingen, San Diego, Calif.,Catalog #555336) and 5 μg/mL anti-CD28 (Immunotech, Beckman Coulter ofBrea Calif., Catalog #IM1376). The primary T-cells were stimulated for3-4 days, then transferred to a fresh flask and maintained in RPMI with% FBS and 40 U/mL IL-2.

Primary T-cells were washed twice with PBS to remove the IL-2 andresuspended in Yssel's medium at 2×10⁶ cells/mL. Cell suspension, 50 μL,containing 80 U/mL IL-2 was added to each well of a flat bottom 96 wellblack plate. For the unstimulated control, IL-2 was omitted from thelast column on the plate. Compounds were serially diluted in dimethylsulfoxide (DMSO, 99.7% pure, cell culture tested, Sigma-Aldrich, St.Louis, Mo., Catalog No. D2650) from 5 mM in 3-fold dilutions, and thendiluted 1:250 in Yssel's medium. Compound, 50 μL per well, was added(done in duplicate, two rows per dilution factor) and the cells wereallowed to proliferate for 72 hours at 37° C.

Proliferation was measured using CellTiter-Glo® Luminescent CellViability Assay (Promega), which determines the number of viable cellsin culture based on quantitation of the ATP present, as an indicator ofmetabolically active cells. The substrate was thawed and allowed to cometo ambient temperature. After mixing the Cell Titer-Glo reagent anddiluent together, 100 μL was added to each well. The plates were mixedon an orbital shaker for two minutes to induce lysis and incubated atambient temperature for an additional ten minutes to allow the signal toequilibrate. Detection was performed using a Wallac Victor2 1420multilabel counter purchased from Perkin Elmer, Shelton, Conn.

Biological Example 3

Stat5 Assay Using Primary Human T-Cells or Mouse T-Cell Leukaemia CTLL-2Cells Stimulated with IL-2

Stimulation of pre-activated primary human T-cells or mouse CTLL-2 cellswith Interleukin-2 (IL-2) signals to JAK-1 and JAK-3 tyrosine kinases tophosphorylate their immediate downstream target, transcription factorStat5. The effects can then be quantified using FACS.

Pre-activated human primary T cells are prepared as described inBiological Example 2. CTLL-2 cells are grown in RPMI containing 10% FBSand 10% T-STIM with Con A (Becton Dickinson).

CTLL-2 cells or human primary T-cells, which have been washed twice withPBS to remove any residual IL-2, are resuspended in RPMI with 10% FBSmedium at 2×10⁶ cells/mL 40 μL of T cells and 50 μL of 2× test compoundare added to each well of a 96-well round-bottom plate and mixed. After1 hour incubation with the text compound at 37° C., the cells arestimulated by addition of 10 μL per well of 10×IL-2 (400 U/mL) so thatthe final concentration is 40 U/mL. Cells are incubated further at 37°C. for 15 min. Stimulation is stopped and cells are fixed by addition of100 μL per well of 3.2% para-formaldehyde and incubation for 10 min atambient temperature. Following a wash, cells are permeabilized byaddition of 150 μL per well of ice-cold methanol and incubation at 4° C.for 30 min. Pelleted cells are washed once with 150 μL per well FACSbuffer (PBS+2% FCS) and stained with 50 μL per well ofanti-phospho-Stat5 AlexaFluor488 1:100 in FACS buffer. Followingovernight incubation at ambient temperature, the samples are analyzed byFACS after initial wash with FACS buffer.

Biological Example 4 Stat5 Assay of Unstimulated Human ErythroleukaemiaSET2 Cells and Mouse Pre-B Ba/F3 Cells Expressing Human V617F JAK2Kinase

Human erythroleukaemia SET2 cells and mouse pre-B Ba/F3 cells bothexpress constitutively active form of JAK2 containing mutation V617F ina pseudokinase domain of the enzyme, leading to constitutivephosphorylation of Stat5 transcription factor in the absence of anystimulation.

40 μL of the corresponding cell suspension and 50 μL of 2× text compoundare mixed together in each well of a 96-well round-bottom plate andincubated for 1 hr at 37° C. The reaction is stopped by addition of 100μL per well of 3.2% para-formaldehyde for 10 min followed bypermeabilization step with 150 mL of ice-cold methanol at 4° C. for 30min. After a wash, the cells are stained with 50 μL per well ofanti-phospho-Stat5 AlexaFluor488 1:100 in FACS buffer. Followingovernight incubation at ambient temperature, the samples are analyzed byFACS.

Biological Example 5 A549 Epithelial Line Stimulated with IFNγ

A549 lung epithelial cells up-regulate ICAM-1 (CD54) surface expressionin response to a variety of different stimuli. Therefore, using ICAM-1expression as readout, compound effects on different signaling pathwayscan be assessed in the same cell type. IFNγ up-regulates ICAM-1 throughactivation of the JAK/Stat pathway. In this example, the up-regulationof ICAM-1 by IFNγ was assessed.

The A549 lung epithelial carcinoma cell line originated from theAmerican Type Culture Collection. Routine culturing was with F12K media(Mediatech Inc., Lenexa, Kans., Cat. No. 10-025-CV) with 10% fetalbovine serum, 100 I.U. penicillin and 100 ng/mL streptomycin (completeF12k media). Cells were incubated in a humidified atmosphere of 5% CO₂at 37° C. Prior to use in the assay, A549 cells were washed with PBS andtrypsinized (Mediatech Inc., Cat. No. 25-052-CI) to lift the cells. Thetrypsin cell suspension was neutralized with complete F12K media andcentrifuged to pellet the cells. The cell pellet was resuspended incomplete F12K media at a concentration of 2.0×10⁵/mL. Cells were seededat 20,000 per well, 100 μL total volume, in a flat bottom tissue cultureplate and allowed to adhere overnight.

On day two, A549 cells were pre-incubated with test compound or DMSO(control) (Sigma-Aldrich, St. Louis, Mo., Catalog No. D2650) for 1 hour.The cells were then stimulated with IFNγ (75 ng/mL) (Peprotech Inc.,Rocky Hill, N.J., Cat. No. 300-02) and allowed to incubate for 24 hours.The final test compound dose range was 30 μM to 14 nM in 200 μL F12Kmedia containing 5% FBS, 0.3% DMSO.

On day three, the cell media was removed and the cells were washed with200 μL PBS (phosphate buffered saline). Each well was trypsinized todissociate the cells, then neutralized by addition of 200 μL completeF12K media. Cells were pelleted and stained with an APC conjugated mouseanti-human ICAM-1 (CD54) (BD Pharmingen, San Diego, Calif., Catalog#559771) antibody for 20 minutes at 4° C. Cells were washed with icecold FACS buffer (PBS+2% FBS) and surface ICAM-1 expression was analyzedby flow cytometry. Detection was performed using a BD LSR I System FlowCytometer, purchased from BD Biosciences of San Jose, Calif. Events weregated for live scatter and the geometric mean was calculated(Becton-Dickinson CellQuest software version 3.3, Franklin Lakes, N.J.).Geometric means were plotted against the compound concentration togenerate a dose response curve.

Biological Example 6 U937 IFNγ ICAM1 FACS Assay

Human U937 monocytic cells up-regulate ICAM-1 (CD54) surface expressionin response to a variety of different stimuli. Therefore, using ICAM-1expression as readout, compound effects on different signaling pathwayscan be assessed in the same cell type. IFNγ up-regulates ICAM-1 throughactivation of the JAK/Stat pathway. In this example, the up-regulationof ICAM-1 by IFNγ was assessed.

The U937 human monocytic cell line was obtained from ATCC of RockvilleMd., catalog number CRL-1593.2, and cultured in RPM1-1640 mediumcontaining 10% (v/v) FCS. U937 cells were grown in 10% RPMI. The cellswere then plated at a concentration of 100,000 cells per 160 μL in 96well flat bottom plates. The test compounds were then diluted asfollows: 10 mM test compound was diluted 1:5 in DMSO (3 μL 10 mM testcompound in 12 μL DMSO), followed by a 1:3 serial dilution of testcompound in DMSO (6 μL test compound serially diluted into 12 μL DMSO togive 3-fold dilutions). Then 4 μL of test compound was transferred to 76μL of 10% RPMI resulting in a 10× solution (100 μM test compound, 5%DMSO). For control wells, 4 μL of DMSO was diluted into 76 μL 10% RPMI.

The assay was performed in duplicate with 8 points (8 3-fold dilutionconcentrations from 10 μL) and with 4 wells of DMSO only (control wells)under stimulated conditions and 4 wells of DMSO only under unstimulatedconditions.

The diluted compound plate was mixed 2× using a multimek (BeckmanCoulter of Brea, Calif.) and then 20 μL of the diluted compounds wastransferred to the 96 well plate containing 160 μL of cells, which werethen mixed again twice at low speeds. The cells and compounds were thenpre-incubated for 30 minutes at 37° C. with 5% CO₂.

The 10× stimulation mix was made by preparing a 100 ng/mL solution ofhuman IFNγ in 10% RPMI. The cells and compound were then stimulated with20 μL of IFNγ stimulation mix to give a final concentration of 10 ng/mLIFNγ, 10 μM test compound, and 0.5% DMSO. The cells were kept underconditions for stimulation for 18-24 hours at 37° C. with 5% CO₂.

The cells were transferred to a 96 well round bottom plate for stainingand then kept on ice for the duration of the staining procedure. Cellswere spun down at 1000 rpm for 5 minutes at 4° C., following which thesupernatant was removed. Following removal of the supernatant, 1 μL APCconjugated mouse anti-human ICAM-1 antibody was added per 100 μL FACSbuffer. The cells were then incubated on ice in the dark for 30 minutes.Following incubation, 150 μL of FACS buffer was added and the cells werecentrifuged at 1000 rpm for 5 minutes at 4° C., following which thesupernatant was removed. After removal of the supernatant, 200 μL ofFACS buffer was added and the cells were resuspended. After suspension,the cells were centrifuged at 1000 rpm for 5 min at 4° C. Supernatantwas then removed prior to resuspension of the cells in 150 μL FACSbuffer.

Detection was performed using a BD LSR I System Flow Cytometer,purchased from BD Biosciences of San Jose, Calif. The live cells weregated for live scatter and the geometric mean of ICAM-APC was measured(Becton-Dickinson CellQuest software version 3.3, Franklin Lakes, N.J.).Both % live cells and ICAM-1 expression was analyzed. The assays for thetest compounds were carried out in parallel with a control compound ofknown activity. The EC₅₀ for the control compound is typically 40-100nM.

Biological Example 7 Fluorescence Polarization Kinase Assay

This assay may be utilized to determine the potency of a compound of theinvention against certain JAK kinases and the selectivity of a compoundof the invention in inhibiting certain JAK kinase activity in vitro.

Reagents and Buffers

Tyrosine Kinase Kit Green (Invitrogen, Cat #P2837)

Acetylated Bovine Gamma Globulin (BGG) (Invitrogen, Cat #P2255)

Active JAK1 (Carna Biosciences)

Active JAK2 (Carna Biosciences)

Active JAK3 (Carna Biosciences)

TK2 Peptide (Biotin-EGPWLEEEEEAYGWMDF-CONH₂) (SynPep Custom Synthesis)

Methods

Test compounds were serially diluted in DMSO starting from 500× thedesired final concentration and then diluted to 1% DMSO in kinase buffer(20 mM HEPES, pH 7.4, 5 mM MgCl₂, 2 mM MnCl₂, 1 mM DTT, 0.1 mg/mLacetylated BGG). Test compound in 1% DMSO (0.2% DMSO final) was mixedwith ATP and substrate in kinase buffer at ambient temperature.

The kinase reactions were performed in a final volume of 20 μLcontaining peptide substrate and ATP and started by addition of kinasein kinase buffer. The reactions were allowed to proceed at ambienttemperature. Final substrate, ATP and enzyme concentrations and reactiontimes for the different kinase assays are listed in Table 1.

TABLE 1 FINAL SUBSTRATE, ATP, ENZYME CONCENTRATIONS AND REACTION TIMESEnzyme Amount Substrate per Concen- ATP Assay Enzyme Reaction Substratetration Concentration Time JAK1  20 ng TK2 10 μM 5 μM 20 min JAK2 0.3 ngTK2 10 μM 5 μM 20 min JAK3   2 ng TK2 10 μM 5 μM 20 min

The reactions were stopped by adding 20 μL of PTK quench mix containingEDTA/anti-phosphotyrosine antibody (1× final)/fluorescent phosphopeptidetracer (0.5× final) diluted in FP Dilution Buffer according tomanufacturer's instructions (Invitrogen). The plates were incubated for30 minutes in the dark at ambient temperature and then read on aPolarion fluorescence polarization plate reader (Tecan).

Data were converted to amount of phosphopeptide present using acalibration curve generated by competition with the phosphopeptidecompetitor provided in the Tyrosine Kinase Assay Kit, Green(Invitrogen). For IC₅₀ determination, the compounds were tested ateleven concentrations in duplicate and curve-fitting was performed bynon-linear regression analysis using Matlab version 6.5 (MathWorks,Inc., Natick, Mass., USA).

Biological Example 8 Proliferation Assay

Reagents and Buffers

Dimethyl Sulfoxide (DMSO) (Sigma-Aldrich, Cat No. D2650) (Control)

Iscove's DMEM, ATCC Catalog #30-2005

1 M HEPES, Cellgro Catalog #25-060-CI (100 mL)

100 mM Sodium Pyruvate, Cellgro Catalog #25-000-CI (100 mL)

Pennicillin/Streptomycin, 10000 U/mL each, Cellgro Catalog #30-002-CI(100 mL)

RPMI 1640 (Cellgro, Cat No. 10-040-CM)

Fetal Bovine Serum (JRH, Cat No. 12106-500M)

Donor Equine Serum, Hyclone Catalog #SH30074.02 (100 mL)

50 μM hydrocortisone solution, Sigma Catalog #H6909-10 ml (10 mL)

Culture Conditions

Ba/F3 V617F cells are maintained and plated in RPMI with 10% FBS.Plating density for these cells is 1×10⁵ cells/mL.

UKE-1 are maintained and plated in Iscove's DMEM containing 10% FBS, 10%equine serum, 1% penicillin/streptomycin and 1 uM hydrocortisone.Plating density for these cells is 0.4×10⁶ cells/mL.

SET2 cells are maintained and plated in RPMI with 20% FBS. Platingdensity for these cells is 2×10⁵ cells/mL.

CTLL-2 cells are maintained and plated in RPMI containing 10% FBS and10% T-STIM with Con A (Becton Dickinson). Plating density for thesecells is 0.4×10⁵ cells/mL

Methods

The cells were resuspended in a corresponding medium at a required celldensity (see above). 100μ of cell suspension was added to each well of aflat bottom 96 well white plate. The compound was serially diluted inDMSO from 5 mM in 3-fold dilutions, and then diluted 1:250 in the RPMI1640 medium containing 5% FBS and pen/strep. 100 μL of resulting 2×compound solution was added per well in duplicate and the cells wereallowed to proliferate for 72 hours at 37° C.

Proliferation was measured using Cell Titer-Glo. The substrate wasthawed and allowed to come to ambient temperature. After removal of top100 μL of medium from each well, 100 μL of the premixed Cell Titer-Gloreagent was added to each well. The plates were mixed on an orbitalshaker for three minutes to induce lysis and incubated at ambienttemperature for an additional five minutes to allow the signal toequilibrate. The Luminescence was read on the Wallac Plate Reader.

The results of the ability of the compounds of the invention to inhibitJAK2 activity, when tested in the above assay utilizing Ba/F3 V617Fcells, are shown in the following Tables 2-3 wherein the level ofactivity (i.e., the IC₅₀) for each compound is indicated in Tables 2-3.The compound numbers in Tables 2-3 refers to the compounds disclosedherein as being prepared by the methods disclosed herein:

TABLE 2 (Ia-1)

Cpd Compound # Name n m R¹ R² R³ R⁴ R⁵ IC₅₀ 1 4-(6-(N,N- dimethylamino)-pyridin-3- yl)-N-(3-methyl- 4-((1S,4S)- 5-methyl- 2,5-diazabicyclo-[2.2.1]heptan-2- yl)phenyl)- pyrimidin- 2-amine 0 1 H —CH₃ —

A 2 4-(6-(N,N- dimethylamino)- pyridin-3- yl)-5-methyl-N- (3-methyl-4-((1S,4S)- 5-methyl-2,5- diazabicyclo- [2.2.1]- heptan-2- yl)phenyl)-pyrimidin- 2-amine 1 1 H —CH₃ —CH₃

A 3 4-(6-(N,N- dimethylamino)- pyridin-3- yl)-5- trifluoromethyl-N-(3-methyl-4- ((1S,4S)-5- methyl-2,5- diazabicyclo- [2.2.1]- heptan-2-yl)phenyl)- pyrimidin- 2-amine 1 1 H —CH₃ —CF₃

B 4 4-(6-(N,N- dimethylamino)- pyridin-3- yl)-5-fluoro-N- (3-methyl-4-((1S,4S)- 5-methyl-2,5- diazabicyclo- [2.2.1]- heptan-2- yl)phenyl)-pyrimidin- 2-amine 1 1 H —CH₃ —F

A 5 4-(6-(N,N- dimethylamino)- pyridin-3- yl)-5-fluoro-N- (3-fluoro-4-((1S,4S)-5- methyl-2,5- diazabicyclo- [2.2.1]- heptan-2- yl)phenyl)-pyrimidin- 2-amine 1 1 H —F —F

B 6 4-(6-(N,N- dimethylamino)- pyridin-3- yl)-5-methyl-N- (3-fluoro-4-((1S,4S)-5- methyl-2,5- diazabicyclo- [2.2.1]- heptan-2- yl)phenyl)-pyrimidin- 2-amine 1 1 H —F —CH₃

A 7 4-(6-(N,N- dimethylamino)- pyridin-3- yl)-N-(3-fluoro- 4-((1S,4S)-5-methyl-2,5- diazabicyclo- [2.2.1]heptan- 2-yl)phenyl)- pyrimidin-2-amine 0 1 H —F —

A 8 4-(4-methyl- 3,4-dihydro- 2H-pyrido- [3,2-b]- [1,4]-oxazin-7-yl)-N-(3- methyl-4- ((1S,4S)-5- methyl-2,5- diazabicyclo- [2.2.1]-heptan-2- yl)phenyl)- pyrimidin- 2-amine 0 1 H —CH₃ —

A 9 4-(4-methyl- 3,4-dihydro- 2H-pyrido- [3,2-b][1,4]- oxazin-7-yl)-N-(3- fluoro-4- ((1S,4S)- 5-methyl-2,5- diazabicyclo- [2.2.1]-heptan-2- yl)phenyl)- pyrimidin- 2-amine 0 1 H —F —

A 10 4-(6- (morpholin-4- yl)pyridin-3- yl)-N-(3- methyl- 4-((1S,4S)-5-methyl-2,5- diazabicyclo- [2.2.1]- heptan-2- yl)phenyl)- pyrimidin-2-amine 0 1 H —CH₃ —

A 11 4-(6- (morpholin-4- yl)pyridin-3- yl)-N-(3- fluoro- 4-((1S,4S)-5-methyl-2,5- diazabicyclo- [2.2.1]- heptan-2- yl)phenyl)- pyrimidin-2-amine 0 1 H —F —

12 4-(6- ((1S,4S)-5- methyl-2,5- diazabicyclo- [2.2.1]- heptan-2-yl)pyridin-3- yl)-N-(3- methyl-4-(4- methyl- piperazin- 1-yl)phenyl)-pyrimidin- 2-amine 0 1 H —CH₃ —

B 13 4-(6- ((1S,4S)-5-(4- fluorophenyl)- 2,5- diazabicyclo- [2.2.1]-heptan-2- yl)pyridin-3- yl)-N-(3- methyl- 4-(4-methyl- piperazin-1-yl)phenyl)- pyrimidin- 2-amine 0 1 H —CH₃ —

A 14 4-(4-(N,N- dimethylamino)- phenyl)-N- (3-methyl-4- ((1S,4S)-5-methyl-2,5- diazabicyclo- [2.2.1]- heptan-2- yl)phenyl)- pyrimidin-2-amine 0 1 H —CH₃ —

A 15 4-(4-(N,N- dimethyl- amino)- phenyl)-N- (3-fluoro-4- ((1S,4S)-5-methyl-2,5- diazabicyclo- [2.2.1]- heptan-2- yl)phenyl)- pyrimidin-2-amine 0 1 H —F —

B 16 4-(6-(4- acetylpiperazin- 1-yl)pyridin- 3-yl)-N- (3-fluoro-4-((1S,4S)-5- methyl-2,5- diazabicyclo- [2.2.1]- heptan-2- yl)phenyl)-pyrimidin- 2-amine 0 1 H —F —

A 19 4-(2,2- dimethyl-3-oxo- 3,4-dihydro- 2H-pyrido[3,2- b][1,4]-oxazin-7-yl)-N- (3-fluoro-4- ((1S,4S)- 5-methyl-2,5- diazabicyclo-[2.2.1]- heptan-2- yl)phenyl)- pyrimidin- 2-amine 0 1 H —F —

A 20 4-(2,2- dimethyl-3- oxo-3,4- dihydro- 2H-pyrido- [3,2-b][1,4]-oxazin-7-yl)-N- (3-methyl-4- ((1S,4S)-5- methyl-2,5- diazabicyclo-[2.2.1]- heptan-2- yl)phenyl)- pyrimidin- 2-amine 0 1 H —CH₃ —

A 21 4-(1H-indol- 6-yl)-N- (3-methyl-4- ((1S,4S)-5- methyl-2,5-diazabicyclo- [2.2.1]- heptan-2- yl)phenyl)- pyrimidin- 2-amine 0 1 H—CH₃ —

A 22 4-(1H- pyrrolo[2,3-b]- pyridin-5-yl)- N-(3-methyl- 4-((1S,4S)-5-methyl-2,5- diazabicyclo- [2.2.1]- heptan-2- yl)phenyl)- pyrimidin-2-amine 0 1 H —CH₃ —

A 23 4-(1H-pyrrolo- [2,3-b]- pyridin-5-yl)- N-(3-fluoro-4- ((1S,4S)-5-methyl-2,5- diazabicyclo- [2.2.1]- heptan-2- yl)phenyl)- pyramidin-2-amine 0 1 H —F —

A 24 4-(6-(dimethyl- amino)- pyridin-3-yl)- N-(3-methyl-4- ((1S,4S)-5-ethyl-2,5- diazbicyclo- [2.2.1]- heptan-2- yl)phenyl)- pyrimidin-2-amine 0 1 H —CH₃ —

A 25 4-(6- (morpholin- 4-yl)-pyridin- 3-yl)-N- (3-methyl-4- ((1S,4S)-5-ethyl-2,5- diazabicyclo- [2.2.1]- heptan-2- yl)phenyl)- pyrimidin-2-amine 0 1 H —CH₃ —

A 26 4-(6- (morpholin- 4-yl)pyridin- 3-yl)-N- (3-methyl-4- ((1S,4S)-5-((ethylamino)- carbonyl)- 2,5- diazabicyclo- [2.2.1]- heptan-2-yl)phenyl)- pyrimidin- 2-amine 0 1 H —CH₃ —

A 27 4-(2,2- dimethyl-3- oxo-3,4- dihydro- 2H-pyrido [3,2-b][1,4]-oxazin-7-yl)- N-(3-methyl- 4-((1S,4S)- 5-oxa-2- azabicyclo- [2.2.1]-heptan-2- yl)phenyl)- pyrimidin- 2-amine 0 1 H —CH₃ —

A 28 4-(2,2- dimethyl-3- oxo-3,4- dihydro- 2H-pyrido- [3,2-b][1,4]-oxazin-7-yl)- N-(3-methyl- 4-((1S,4S)-5- (ethyl- carbonyl)-2,5-diazabicyclo- [2.2.1]- heptan-2- yl)phenyl)- pyrimidin- 2-amine 0 1 H—CH₃ —

A 29 4-(2,2- dimethyl-3- oxo-3,4- dihydro- 2H-pyrido- [3,2-b][1,4]-oxazin-7-yl)- N-(3-methyl- 4-((1S,4S)-5- (methyl- sulfonyl)-2,5-diazabicyclo- [2.2.1]- heptan-2- yl)phenyl)- pyrimidin- 2-amine 0 1 H—CH₃ —

A 30 4-(2,2- dimethyl-3- oxo-3,4- dihydro- 2H-pyrido- [3,2-b][1,4]-oxazin-7-yl)- N-(3-methyl- 4-((1S,4S)- 5-ethyl-2,5- diazabicyclo-[2.2.1]- heptan-2- yl)phenyl)- pyrimidin- 2-amine 0 1 H —CH₃ —

A 31 4-(3′-oxo- 3′,4′- dihydrospiro- [cyclobutane- 1,2′-pyrido-[3,2-b][1,4]- oxazine]-7′- yl)-N-(3- methyl-4- ((1S,4S)- 5-methyl-2,5-diazabicyclo- [2.2.1]- heptan-2- yl)phenyl)- pyrimidin- 2-amine 0 1 H—CH₃ —

A 32 4-(3′-oxo- 3′,4′- dihydrospiro- [cyclobutane- 1,2′-pyrido-[3,2-b][1,4]- oxazine]-7′- yl)-N-(3- methyl-4- ((1S,4S)- 5-ethyl-2,5-diazabicyclo- [2.2.1]- heptan-2- yl)phenyl)- pyrimidin- 2-amine 0 1 H—CH₃ —

A 33 4-(1H-pyrrolo- [2,3-b]- pyridin-5- yl)-N- (3-methyl- 4-((1S,4S)-5-oxa-2- azabicyclo- [2.2.1]- heptan-2- yl)phenyl)- pyrimidin- 2-amine 01 H —CH₃ —

A 34 4-(1H- pyrrolo[2,3-b]- pyridin-5-yl)- N-(3-methyl- 4-((1S,4S)-5-(2,2,2- trifluoro- ethyl)-2,5- diazabicyclo- [2.2.1]- heptan-2-yl)phenyl)- pyrimidin- 2-amine 0 1 H —CH₃ —

A 35 4-(1H-pyrrolo- [2,3-b]pyridin- 5-yl)-N- (3-methyl-4- ((1S,4S)-5-(cyclopropyl)- methyl-2,5- diazabicyclo- [2.2.1]- heptan-2- yl)phenyl)-pyrimidin- 2-amine 0 1 H —CH₃ —

A 36 4-(6- (morpholin-4- yl)pyridin-3- yl)-N-(3- methyl-4- ((1S,4S)-5-(2,2,2- trifluoroethyl)- 2,5- diazabicyclo- [2.2.1]- heptan-2-yl)phenyl)- pyrimidin- 2-amine 0 1 H —CH₃ —

B 37 4-(6- (morpholin-4- yl)pyridin-3- yl)-N-(3- methyl-4- ((1S,4S)-5-(cyclopropyl)- methyl-2,5- diazabicyclo- [2.2.1]- heptan-2- yl)phenyl)-pyrimidin- 2-amine 0 1 H —CH₃ —

A 38 4-(2,2- dimethyl-3- oxo-3,4- dihydro- 2H-pyrido- [3,2-n][1,4]-oxazin-7-yl)- N-(3-methyl-4- ((1S,4S)-5- (amino- sulfonyl)-2,5-diazabicyclo- [2.2.1]- heptan-2- yl)phenyl)- pyrimidin- 2-amine 0 1 H—CH₃ —

A 39 4-(3-fluoro-2- (morpholin-4- yl)pyridin- 4-yl)-N-(3- fluoro-4-((1S,4S)-5- methyl-2,5- diazabicyclo- [2.2.1]- heptan-2- yl)phenyl)-pyrimidin- 2-amine 0 1 H —F —

B 40 4-(2- (morpholin-4- yl)pyrimidin- 5-yl)-N- (4-((1S,4S)-5-methyl-2,5- diazabicyclo- [2.2.1]- heptan-2- yl)phenyl)- pyrimidin-2-amine 0 0 H — —

B 41 4-(2- (morpholin-4- yl)pyrimidin- 5-yl)-N-(3- methyl-4- ((1S,4S)-5-methyl-2,5- diazabicyclo- [2.2.1]heptan-2- yl)phenyl)- pyrimidin-2-amine 0 1 H —CH₃ —

A 42 4-(2- (morpholin-4- yl)pyrimidin- 5-yl)-N-(3- methyl-4- ((1S,4S)-5-oxa-2- azabicyclo- [2.2.1]- heptan-2- yl)phenyl)- pyrimidin- 2-amine 0 1H —CH₃ —

B 43 4-(2- (morpholin-4- yl)pyrimidin- 5-yl)-N-(3- fluoro-4- ((1S,4S)-5-methyl-2,5- diazabicyclo- [2.2.1]- heptan-2- yl)phenyl)- pyrimidin-2-amine 0 1 H —F —

A 44 4-(2-((cyclo- propyl)- carbonyl- amino)- pyrimidin- 5-yl)-N-(3-methyl-4- ((1S,4S)-5- methyl-2,5- diazabicyclo- [2.2.1]- heptan-2-yl)phenyl)- pyrimidin- 2-amine 0 1 H —CH₃ —

A 45 4-(4-(4,5- dihydro- thiazol-2- ylcarbamoyl)- phenyl)-N-(3-methyl-4- ((1S,4S)-5- methyl-2,5- diazabicyclo- [2.2.1]- heptan-2-yl)phenyl)- pyrimidin- 2-amine 0 1 H —CH₃ —

B 46 4-(4-(1,1- dimethyl- ethyl)- phenyl)-N- (3-methyl-4- ((1S,4S)-5-methyl-2,5- diazabicyclo- [2.2.1]- heptan-2- yl)phenyl)- pyrimidin-2-amine 0 1 H —CH₃ —

A 47 4-(4- (morpholin-4- yl)phenyl)-N- (3-fluoro-4- ((1S,4S)-5-methyl-2,5- diazabicyclo- [2.2.1]- heptan-2- yl)phenyl)- pyrimidin-2-amine. TFA salt 0 1 H —F —

B 48 4-(4-((methyl)- amino- carbonyl- methyl)- phenyl)-N- (3-methyl-4-((1S,4S)-5- methyl-2,5- diazabicyclo- [2.2.1]- heptan-2- yl)phenyl)-pyrimidin- 2-amine. TFA salt 0 1 H —CH₃ —

B 49 4-(4-((cyclo-propyl)- amino- carbonyl- methyl)- phenyl)-N-(3-methyl- 4-((1S,4S)-5- methyl-2,5- diazabicyclo- [2.2.1]- heptan-2-yl)phenyl)- pyrimidin- 2-amine 0 1 H —CH₃ —

B 50 4-(6-(methylamino- carbonyl)- pyridin- 3-yl)-N- (3-methyl-4-((1S,4S)-5- methyl-2,5- diazabicyclo- [2.2.1]- heptan-2- yl)phenyl)-pyrimidin-2- amine 0 1 H —CH₃ —

A 51 4-(7-oxo-, 5,6,7,8- tetrahydro- 1,8- naphthyridin- 3-yl)-N-(3-methyl-4- ((1S,4S)-5- methyl-2,5- diazabicyclo- [2.2.1]- heptan-2-yl)phenyl)- pyrimidin-2- amine. TFA salt 0 1 H —CH₃ —

A 52 4-(5- ((morpholin-4- yl)carbonyl)- pyridin- 3-yl)-N-(3- methyl-4-((1S,4S)- 5-methyl-2,5- diazabicyclo- [2.2.1]- heptan-2- yl)phenyl)-pyrimidin- 2-amine. Bis TFA salt 0 1 H —CH₃ —

A 53 4-(2,2- dimethyl-3- oxo-3,4- dihydro- 2H-pyrido- [3,2-b][1,4]-oxazin-7-yl)- N-(3-cyano- 4-((1S,4S)- 5-methyl-2,5- diazabicyclo-[2.2.1]- heptan-2- yl)phenyl)- pyrimidin- 2-amine 0 1 H -CN —

A 59 4-(5-methyl- 6-(morpholin- 4-yl)pyridin- 3-yl)-N-(3- fluoro-4-((1S,4S)-5- methyl-2,5- diazabicyclo- [2.2.1]- heptan-2- yl)phenyl)-pyrimidin- 2-amine 0 1 H —F —

A 60 4-(5-methyl- 6-(morpholin- 4-yl)pyridin- 3-yl)-N-(3- methyl-4-((1S,4S)-5- methyl-2,5- diazabicyclo- [2.2.1]- heptan-2- yl)phenyl)-pyrimidin- 2-amine 0 1 H —CH₃ —

A 67 5-methyl-4-(6- (morpholin-4- yl)pyridin-3- yl)-N- (3-methyl-4-((1S,4S)-5- methyl-2,5- diazabicyclo- [2.2.1]- heptan-2- yl)phenyl)-pyrimidin- 2-amine 1 1 H —CH₃ —CH₃

A 68 5-methyl-4- (6-(morpholin- 4-yl)pyridin- 3-yl)-N- (3-fluoro-4-((1S,4S)-5- methyl-2,5- diazabicyclo- [2.2.1]- heptan-2- yl)phenyl)-pyrimidin- 2-amine 1 1 H —F —CH₃

A 69 4-(6-(2- (morpholin-4- yl)ethyl)- aminopyridin- 3-yl)-N-(4-((1S,4S)-5- methyl-2,5- diazabicyclo- [2.2.1]- heptan-2- yl)phenyl)-pyrimidin- 2-amine 0 0 H — —

B 70 4-(6-(2- (morpholin-4- yl)ethyl)- aminopyridin- 3-yl)-N- (3-fluoro-4-((1S,4S)- 5-methyl-2,5- diazabicyclo- [2.2.1]- heptan-2- yl)phenyl)-pyrimidin- 2-amine 0 1 H —F —

A 71 4-(2,2- dimethyl-3- oxo-3,4- dihydro- 2H-pyrido [3,2-b][1,4]-oxazin-7-yl)- N-(3-methyl- 4-((1R,4R)- 5-methyl-2,5- diazabicyclo-[2.2.1]- heptan-2- yl)phenyl)- pyrimidin- 2-amine 0 1 H —CH₃ —

A 72 4-(6- (morpholin- 4-yl)pyridin- 3-yl)-N- (3-methyl-4- ((1R,4R)-5-methyl-2,5- diazabicyclo- [2.2.1]- heptan-2- yl)phenyl)- pyrimidin-2-amine 0 1 H —CH₃ —

A 73 4-(2,2- dimethyl-3- oxo-3,4- dihydro- 2H-pyrido [3,2-b][1,4]-oxazin-7-yl)- N-(3-fluoro- 4-((1R,4R)- 5-methyl-2,5- diazabicyclo-[2.2.1]- heptan-2- yl)phenyl)- pyrimidin- 2-amine 0 1 H F —

A 74 4-(6- (morpholin- 4-yl)pyridin- 3-yl)-N- (3-fluoro-4- ((1R,4R)-5-methyl-2,5- diazabicyclo- [2.2.1]- heptan-2- yl)phenyl)- pyrimidin-2-amine 0 1 H F —

A 75 4-(6- (morpholin-4- yl)pyridin- 3-yl)-N- (3-methyl-4- (1,5,7-trimethyl-3,7- diazabicyclo- [3.3.1]- nonan-3- yl)phenyl)- pyrimidin-2-amine 0 1 H —CH₃ —

A 76 4-(6- (dimethyl- amino)- pyridin-3-yl)- N-(3-methyl- 4-(1,5,7-trimethyl-3,7- diazabicyclo- [3.3.1]- nonan-3- yl)phenyl)- pyrimidin-2-amine 0 1 H —CH₃ —

A 77 4-(6-(cyclo- hexylamino)- pyridin-3-yl)- N-(3-methyl- 4-(1,5,7-trimethyl-3,7- diazabicyclo- [3.3.1]- nonan-3- yl)phenyl)- pyrimidin-2-amine 0 1 H —CH₃ —

A 78 4-(6-(cyclo- hexylamino)- pyridin-3-yl)- N-(3-methyl- 4-((1S,4S)-5-methyl- 2,5-diazabicyclo- [2.2.1]heptan-2- yl)phenyl)- pyrimidin-2-amine 0 1 H —CH₃ —

A 79 4-(6-(cyclo- hexylamino)- pyridin-3-yl)- N-(3-fluoro- 4-((1S,4S)-5-methyl-2,5- diazabicyclo- [2.2.1]- heptan-2- yl)phenyl)- pyrimidin-2-amine 0 1 H —F —

A 80 4-(6-(benzyl)- pyridin- 3-yl)-N-(3- methyl-4- ((1S,4S)-5-methyl-2,5- diazabicyclo- [2.2.1]- heptan-2- yl)phenyl)- pyrimidin-2-amine 0 1 H —CH₃ —

A 81 4-(6-(benzyl)- pyridin- 3-yl)-N-(3- fluoro-4- ((1S,4S)-5-methyl-2,5- diazabicyclo- [2.2.1]- heptan-2- yl)phenyl)- pyrimidin-2-amine 0 1 H —F —

A 82 4-(5-methyl-6- (morpholin-4- yl)pyridin-3- yl)-N-(3-fluoro-4-(1,5,7- trimethyl-3,7- diazabicyclo- [3.3.1]- nonan-3-yl)phenyl)- pyrimidin- 2-amine 0 1 H —F —

A 83 4-(6- (dimethyl- amino)- pyridin-3- yl)-N-(3- fluoro-4- (1,5,7-trimethyl-3,7- diazabicyclo- [3.3.1]- nonan-3- yl)phenyl)- pyrimidin-2-amine 0 1 H —F —

A 84 4-(4- (dimethyl- amino)- phenyl)-N- (3-fluoro-4- (1,5,7-trimethyl-3,7- diazabicyclo- [3.3.1]- nonan-3- yl)phenyl)- pyrimidin-2-amine 0 1 H —F —

A 85 4-(6- (morpholin-4- yl)pyridin-3- yl)-N-(3- fluoro-4- (1,5,7-trimethyl-3,7- diazabicyclo- [3.3.1]- nonan-3- yl)phenyl)- pyrimidin-2-amine 0 1 H —F —

A 86 4-(3,4- dihydro- 2H-pyrido [3,2-b][1,4]- oxazin-7- yl)-N-(3-methyl-4- ((1S,4S)-5- methyl-2,5- diazabicyclo- [2.2.1]- heptan-2-yl)phenyl)- pyrimidin- 2-amine 0 1 H —CH₃ —

A 87 4-(3,4- dihydro- 2H-pyrido- [3,2-b][1,4]- oxazin-7- yl)-N-(3-fluoro-4- ((1S,4S)-5- methyl-2,5- diazabicyclo- [2.2.1]- heptan-2-yl)phenyl)- pyrimidin- 2-amine 0 1 H —F —

A 88 4-(3,4- dihydro- 2H-pyrido- [3,2-b][1,4]- oxazin-7-yl)-N-(3-methyl- 4-(1,5,7- trimethyl-3,7- diazabicyclo- [3.3.1]- nonan-3-yl)phenyl)- pyrimidin- 2-amine 0 1 H —CH₃ —

A 89 4-(3,4- dihydro- 2H-pyrido- [3,2-b][1,4]- oxazin-7-yl)-N-(3-fluoro- 4-(1,5,7- trimethyl-3,7- diazabicyclo- [3.3.1]- nonan-3-yl)phenyl)- pyrimidin- 2-amine 0 1 H —F —

B 90 4-(6-(benzyl)- pyridin- 3-yl)-N-(3- methyl-4- (1,5,7-trimethyl-3,7- diazabicyclo- [3.3.1]- nonan-3- yl)phenyl)- pyrimidin-2-amine 0 1 H —CH₃ —

A 91 4-(6-(benzyl)- pyridin-3-yl)- N-(3-fluoro- 4-(1,5,7- trimethyl-3,7-diazabicyclo- [3.3.1]- nonan-3- yl)phenyl)- pyrimidin- 2-amine 0 1 H —F—

A 92 4-(2-(propyl)- amino- pyrimidin- 5-yl)-N- (3-methyl- 4-((1S,4S)-5-methyl-2,5- diazabicyclo- [2.2.1]- heptan-2- yl)phenyl)- pyrimidin-2-amine 0 1 H —CH₃ —

A 93 4-(2-(propyl)- amino- pyrimidin- 5-yl)-N- (3-fluoro-4- ((1S,4S)-5-methyl-2,5- diazabicyclo- [2.2.1]- heptan-2- yl)phenyl)- pyrimidin-2-amine 0 1 H —F —

A 94 4-(6- (cyclohexyl- amino)- pyridin- 3-yl)-N-(3- trifluoro- methyl-4-((1S,4S)-5- methyl-2,5- diazabicyclo- [2.2.1]- heptan-2- yl)phenyl)-pyrimidin- 2-amine 0 1 H —CH₃ —

A 95 4-(5-methyl)- sulfonyl- pyridin-3-yl)- N-(3-methyl- 4-((1S,4S)-5-methyl-2,5- diazabicyclo- [2.2.1]- heptan-2- yl)phenyl)- pyrimidin-2-amine 0 1 H —CH₃ —

A 96 4-(6- (dimethyl- amino)- pyridin-3-yl)- N-(3-tri- fluoromethyl-4-((1S,4S)-5- methyl-2,5- diazabicyclo- [2.2.1]- heptan-2- yl)phenyl)-pyrimidin- 2-amine 0 1 H —CF₃ —

A 97 4-(6- (morpholin-4- yl)pyridin-3- yl)-N-(3-tri- fluoromethyl-4-((1S,4S)-5- methyl-2,5- diazabicyclo- [2.2.1]- heptan-2- yl)phenyl)-pyrimidin- 2-amine 0 1 H —CF₃ —

A 98 4-(3,4-dihydro- 2H-pyrido[3,2- b][1,4]oxazin- 7-yl)-N-(3-trifluoromethyl- 4-((1S,4S)-5- methyl-2,5- diazabicyclo- [2.2.1]heptan-2-yl)phenyl)- pyrimidin- 2-amine 0 1 H —CF₃ —

A 99 4-(6-((2- (cyclopropyl- sulfonyl)- aminoethyl)- amino)pyridin-3-yl)-N- (3-methyl-4- ((1S,4S)-5- methyl-2,5- diazabicyclo- [2.2.1]-heptan-2- yl)phenyl)- pyrimidin- 2-amine 0 1 H —CH₃ —

B 100 4-(6-((2- (cyclopropyl- sulfonyl)- aminoethyl)- amino)pyridin-3-yl)-N-(3- methyl-4- ((1S,4S)-5- oxa-2- azabicyclo- [2.2.1]- heptan-2-yl)phenyl)- pyrimidin- 2-amine 0 1 H —CH₃ —

A 101 4-(5-(methyl)- sulfonyl- pyridin-3-yl)- N-(3-fluoro-4- ((1S,4S)-5-methyl-2,5- diazabicyclo- [2.2.1]- heptan-2- yl)phenyl)- pyrimidin-2-amine 0 1 H —F —

A 102 4-(5-(methyl)- sulfonyl- pyridin- 3-yl)-N-(3-tri- fluoromethyl-4-((1S,4S)-5- methyl-2,5- diazabicyclo- [2.2.1]- heptan-2- yl)phenyl)-pyrimidin- 2-amine 0 1 H —CF₃ —

A 103 4-(imidazo- [1,2-a]pyridin- 6-yl)-N-(3- methyl-4- ((1S,4S)-5-methyl-2,5- diazabicyclo- [2.2.1]- heptan-2- yl)phenyl)- pyrimidin-2-amine 0 1 H —CH₃ —

A 104 4-(4-(5-(4- dimethyl- aminophenyl)- oxazol-2- yl)phenyl)-N-(3-methyl- 4-((1S,4S)-5- methyl-2,5- diazabicyclo- [2.2.1]- heptan-2-yl)phenyl)- pyrimidin- 2-amine 0 1 H —CH₃ —

B 105 4-(6- methoxy-1H- indol-2-yl)- N-(3-methyl- 4-((1S,4S)-5-methyl-2,5- diazabicyclo- [2.2.1]- heptan-2- yl)phenyl)- pyrimidin-2-amine 0 1 H —CH₃ —

A 106 4-(1-(3- chloro- phenyl)- 1H-pyrazol- 4-yl)-N-(3- methyl-4-((1S,4S)-5- methyl-2,5- diazabicyclo- [2.2.1]heptan-2- yl)phenyl)-pyrimidin- 2-amine 0 1 H —CH₃ —

B 107 4-(1-methyl- benzimidazol- 6-yl)-N-(3- methyl-4- ((1S,4S)-5-methyl-2,5- diazabicyclo- [2.2.1]- heptan-2- yl)phenyl)- pyrimidin-2-amine 0 1 H —CH₃ —

A 108 4-(5-cyano- 1H-indol-2- yl)-N-(3- methyl-4- ((1S,4S)-5-methyl-2,5- diazabicyclo- [2.2.1]- heptan-2- yl)phenyl)- pyrimidin-2-amine 0 1 H —CH₃ —

A 109 4-(1-(4- fluoro- phenyl)-1H- pyrazol-4- yl)-N-(3- methyl-4-((1S,4S)-5- methyl-2,5- diazabicyclo- [2.2.1]heptan-2- yl)phenyl)-pyrimidin- 2-amine 0 1 H —CH₃ —

A 110 4-(6- (morpholin-4- yl)pyridin-3- yl)-N-(3- methyl-4-(7-azabicyclo- [2.2.1]- heptan-7- yl)phenyl)- pyrimidin- 2-amine 0 1 H —CH₃—

B 111 4-(6-cyano- pyridin-3-yl)- N-(3-methyl- 4-((1S,4S)-5- methyl-2,5-diazabicyclo- [2.2.1]- heptan-2- yl)phenyl)- pyrimidin- 2-amine 0 1 H—CH₃ —

B 112 4-(6-cyano- pyridin-3-yl)- N-(3-methyl- 4-(7- azabicyclo-[2.2.1]heptan- 7-yl)phenyl)- pyrimidin- 2-amine 0 1 H —CH₃ —

B 113 4-(2- oxoindolin-5- yl)-N-(3- methyl-4- ((1S,4S)-5- methyl-2,5-diazabicyclo- [2.2.1]- heptan-2- yl)phenyl)- pyrimidin- 2-amine 0 1 H—CH₃ —

A 114 4-(5-cyano- pyridin- 3-yl)-N-(3- methyl- 4((1S,4S)-5- methyl-2,5-diazabicyclo- [2.2.1]- heptan-2- yl)phenyl)- pyrimidin- 2-amine 0 1 H—CH₃ —

B 115 4-(6-(1H- tetrazol-5- yl)pyridin-3- yl)-N-(3- methyl-4- ((1S,4S)-5-methyl-2,5- diazabicyclo- [2.2.1]- heptan-2- yl)phenyl)- pyrimidin-2-amine 0 1 H —CH₃ —

C 116 4-(6- (morpholin-4- yl)pyridin-3- yl)-N-(3-cyano- 4-((1S,4S)-5-acetyl-2,5- diazabicyclo- [2.2.1]- heptan-2- yl)phenyl)- pyrimidin-2-amine 0 1 H —CN —

A 117 4-(6- (morpholin-4- yl)pyridin-3- yl)-N-(3- cyano-4- ((1S,4S)-5-methyl- sulfonyl-2,5- diazabicyclo- [2.2.1]- heptan-2- yl)phenyl)-pyrimidin- 2-amine 0 1 H —CN —

A 118 4-(6- (morpholin-4- yl)pyridin-3- yl)-N-(3- cyano-4- ((1S,4S)-5-methyl-2,5- diazabicyclo- [2.2.1]- heptan-2- yl)phenyl)- pyrimidin-2-amine 0 1 H —CN —

A 119 4-(6- (morpholin-4- yl)pyridin-3- yl)-N-(3- cyano-4- ((1S,4S-5-cyclopentyl- 2,5- diazabicyclo- [2.2.1]- heptan-2- yl)phenyl)-pyrimidin- 2-amine 0 1 H —CN —

A 120 4-(6- (morpholin-4- yl)pyridin-3- yl)-N-(3- methyl-4- (1,4-diazabicyclo- [3.2.1]- octan-4- yl)phenyl)- pyrimidin- 2-amine 0 1 H—CH₃ —

A 121 4-(2- oxoindolin-5- yl)-N-(3- methyl-4-(1,4- diazabicyclo-[3.2.1]octan-4- yl)phenyl)- pyrimidin- 2-amine 0 1 H —CH₃ —

A 122 (1-methyl- benzimidazol- 6-yl)-N-(3- methyl-4-(1,4- diazabicyclo-[3.2.1]- octan-4- yl)phenyl)- pyrimidin- 2-amine 0 1 H —CH₃ —

A 123 4-(imidazo [1,2-a]pyridin- 6-yl)-N-(3- methyl-4- (1,4-diazabicyclo- [3.2.1]- octan-4- yl)phenyl)- pyrimidin- 2-amine 0 1 H—CH₃ —

A 124 4-(2H- benzo[b][1,4]- oxazin-3(4H)- on-6-yl)-N- (3-fluoro-4-((1S,4S)-5- methyl-2,5- diazabicyclo- [2.2.1]- heptan-2- yl)phenyl)-pyrimidin- 2-amine 0 1 H —F —

A 125 4-(2,2,4- trimethyl- 3-oxo-3,4-dihydro- 2H-pyrido- [3,2-b][1,4]-oxazin-7-yl)- N-(3-methyl- 4-((1S,4S)- 5-methyl-2,5- diazabicyclo-[2.2.1]- heptan-2- yl)phenyl)- pyrimidin- 2-amine 0 1 H —CH₃ —

A 126 4-(2,2,4- trimethyl-3- oxo-3,4- dihydro- 2H-pyrido- [3,2-b][1,4]-oxazin-7-yl)- N-(3-fluoro-4- ((1S,4S)- 5-methyl-2,5- diazabicyclo-[2.2.1]- heptan-2- yl)phenyl)- pyrimidin- 2-amine 0 1 H —F —

A 127 4-(5-(3- methyl- piperidin- 1-yl)pyrazin- 2-yl)-N- (3-fluoro-4-((1S,4S)-5- methyl-2,5- diazabicyclo- [2.2.1]- heptan-2- yl)phenyl)-pyrimidin- 2-amine 0 1 H —F —

B 128 4-(4-(t- butylcarbonyl- amino)- phenyl)- N-(3-fluoro-4-((1S,4S)-5- methyl-2,5- diazabicyclo- [2.2.1]- heptan-2- yl)phenyl)-pyrimidin- 2-amine 0 1 H —F —

A 129 4-(4-(t- butylcarbonyl- amino)phenyl)- N-(3-methyl-4- ((1S,4S)-5-methyl-2,5- diazabicyclo- [2.2.1]heptan- 2-yl)phenyl)- pyrimidin-2-amine 0 1 H —CH₃ —

A 130 4-(2,2- dimethyl- 3-oxo-3,4-dihydro- 2H-pyrido- [3,2-b][1,4]-oxazin-7-yl)- N-(3-methyl- 4-((1S,4S)-5- methyl-2,5- diazabicyclo-[2.2.1]- heptan-2- yl)phenyl)- pyrimidin- 2-amine 0 1 H —CH₃ —

A 132 4-(6- (acetamido)- pyridin-3-yl)- N-(3-methyl- 4-((1S,4S)-5-methyl-2,5- diazabicyclo- [2.2.1]- heptan-2- yl)phenyl)- pyrimidin-2-amine 0 1 H —CH₃ —

A 133 4-(4-((pyridin- 2-yl)amino- carbonyl)- phenyl)-N-(3- fluoro-4-((1S,4S)- 5-methyl-2,5- diazabicyclo- [2.2.1]- heptan-2- yl)phenyl)-pyrimidin- 2-amine 0 1 H —F —

B 134 4-(4-((pyridin- 2-yl)amino- carbonyl)- phenyl)-N- (3-methyl-4-((1S,4S)- 5-methyl-2,5- diazabicyclo- [2.2.1]- heptan-2- yl)phenyl)-pyrimidin- 2-amine 0 1 H —CH₃ —

A 135 4-(4- (methyl- sulfonyl- amino)- phenyl)- N-(3-fluoro-4-((1S,4S)-5- methyl-2,5- diazabicyclo- [2.2.1]- heptan-2- yl)phenyl)-pyrimidin- 2-amine 0 1 H —F —

A 136 4-(4- (methyl- sulfonyl- amino)- phenyl)-N- (3-methyl-4-((1S,4S)-5- methyl-2,5- diazabicyclo- [2.2.1]heptan- 2-yl)phenyl)-pyrimidin- 2-amine 0 1 H —CH₃ —

A 137 4-(2,2- dimethyl-3- oxo-3,4- dihydro- 2H-pyrido- [3,2-b][1,4]-oxazin-7-yl)- N-(4-((1S,4S)- 5-methyl-2,5- diazabicyclo- [2.2.1]-heptan-2- yl)phenyl)- pyrimidin- 2-amine 0 0 H — —

A 139 4-(4-(3- cyclopropyl- ureido) phenyl)-N- (4-((1S,4S)-5-methyl-2.5- diazabicyclo- [2.2.1]- heptan-2- yl)phenyl)- pyrimidin-2-amine 0 0 H — —

A 141 4-(6-(2- (morpholin-4- yl)acetamido)- pyridin- 3-yl)-N-(3-methyl-4- ((1S,4S)- 5-methyl-2,5- diazabicyclo- [2.2.1]- heptan-2-yl)phenyl)- pyrimidin- 2-amine 0 1 H —CH₃ —

A 142 4-(6-(2- (morpholin-4- yl)acetamido)- pyridin-3-yl)- N-(4-((1S,4S)-5- methyl-2,5- diazabicyclo- [2.2.1]- heptan-2- yl)phenyl)-pyrimidin- 2-amine 0 0 H — —

B 143 4-(6-(2- (morpholin-4- yl)acetamido)- pyridin- 3-yl)-N-(3-fluoro-4- ((1S,4S-5- methyl-2,5- diazabicyclo- [2.2.1]- heptan-2-yl)phenyl)- pyrimidin- 2-amine 0 1 H —F —

B 147 4-(6- (acetamido)- pyridin-3- yl)-N-(3- methyl-4- ((1S,4S)-5-oxa-2- azabicyclo- [2.2.1]- heptan-2- yl)phenyl)- pyrimidin- 2-amine 0 1H —CH₃ —

A 148 4-(6-aminopyridin- 3-yl)-N-(3- methyl- 4-((1S,4S)- 5-ethyl-carbonyl-2,5- diazabicyclo- [2.2.1]- heptan-2- yl)phenyl)- pyrimidin-2-amine 0 1 H —CH₃ —

A 149 4-(6- (acetamido)- pyridin-3-yl)- N-(3- methyl-4- ((1S,4S)-5-ethyl- carbonyl-2,5- diazabicyclo- [2.21]heptan- 2-yl)phenyl)-pyrimidin- 2-amine 0 1 H —CH₃ —

A 150 4-(6-amino- pyridin-3- yl)-N-(3- methyl-4- ((1S,4S)-5- methyl-sulfonyl-2,5- diazabicyclo- [2.2.1]- heptan-2- yl)phenyl)- pyrimidin-2-amine 0 1 H —CH₃ —

A 151 4-(6-(methyl- sulfonyl- amino)- pyridin-3- yl)-N-(3- methyl-4-((1S,4S)-5- methyl-2,5- diazabicyclo- [2.2.1]heptan- 2-yl)phenyl)-pyrimidin- 2-amine 0 1 H —CH₃ —

B 152 4-(6-(2- (dimethyl- amino)- acetamido)- pyridin-3-yl)-N-(3-methyl- 4-((1S,4S)- 5-methyl-2,5- diazabicyclo- [2.2.1]- heptan-2-yl)phenyl)- pyrimidin- 2-amine 0 1 H —CH₃ —

A 153 4-(6-(methyl- sulfonyl- amino)- pyridin-3- yl)-N-(3- fluoro-4-((1S,4S)-5- methyl-2,5- diazabicyclo- [2.2.1]heptan- 2-yl)phenyl)-pyrimidin- 2-amine 0 1 H —F —

B 155 4-(6- (morpholin-4- yl)pyridin-3- yl)-N-(4-(8- methyl-3,8-diazabicyclo- [3.2.1]- octan-3- yl)phenyl)- pyrimidin- 2-amine 0 0 H — —

A 156 4-(6-(methyl- sulfonyl- amino)pyridin- 3-yl)-N-(4-(8- methyl-3,8-diazabicyclo- [3.2.1]- octan-3- yl)phenyl)- pyrimidin- 2-amine 0 0 H — —

B 157 4-(2,2- dimethyl-3- oxo-3,4- dihydro- 2H-pyrido- [3,2-b][1,4]-oxazin-7-yl)- N-(4-(8- methyl-3,8- diazabicyclo- [3.2.1]- octan-3-yl)phenyl)- pyrimidin- 2-amine 0 0 H — —

A 158 4-(6-amino- pyridin-3- yl)-N-(4-(8- methyl-3,8- diazabicyclo-[3.2.1]- octan- 3-yl)phenyl)- pyrimidin- 2-amine 0 0 H — —

A 159 4-(6- (morpholin-4- yl)pyridin-3- yl)-N-(3- methyl-4-(1,4-diazabicyclo- [3.2.2]- nonan-4- yl)phenyl)- pyrimidin- 2-amine 0 1 H—CH₃ —

A 160 4-(2,2- dimethyl- 3-oxo-3,4-dihydro- 2H-pyrido[3,2- b][1,4]oxazin-7-yl)-N- (3-methyl- 4-(1,4- diazabicyclo- [3.2.2]- nonan-4- yl)phenyl)-pyrimidin- 2-amine 0 1 H —CH₃ —

A 161 4-(4- ((pyridin-2-yl)- aminocarbonyl)- phenyl)-N-(3-methyl-4-(1,4- diazabicyclo- [3.2.2]- nonan-4- yl)phenyl)- pyrimidin-2-amine 0 1 H —CH₃ —

A 162 4-(4- (acetamido)- phenyl)-N- (4-(8-methyl- 3,8- diazabicyclo-[3.2.1]- octan- 3-yl)phenyl)- pyrimidin-2- amine 0 0 H — —

A 163 4-(2- (diethylamino)- thiazol-4-yl)- N-(3-methyl- 4-((1S,4S-5-methyl-2,5- diazabicyclo- [2.2.1]- heptan-2- yl)phenyl)- pyrimidin-2-amine 0 1 H —CH₃ —

A 164 4-(2- (diethylamino)- thiazol-4-yl)- N-(3-fluoro-4- ((1S,4S)-5-methyl-2,5- diazabicyclo- [2.2.1]- heptan-2- yl)phenyl)- pyrimidin-2-amine 0 1 H —F —

A 165 4-(2,2- dimethyl-3- oxo-3,4- dihydro- 2H-pyrido[3,2-b][1,4]oxazin- 7-yl)-N- (3-methyl-4- (8-methyl-3,8- diazabicyclo-[3.2.1]- octan-3- yl)phenyl)- pyrimidin- 2-amine 0 1 H —CH₃ —

A 166 4-(6- (morpholin-4- yl)pyridin-3- yl)-N-(3- methyl-4-(8-methyl-3,8- diazabicyclo- [3.2.1]- octan-3- yl)phenyl)- pyrimidin-2-amine 0 1 H —CH₃ —

A 167 4-(6-(methyl- sulfonyl- amino)pyridin- 3-yl)-N-(3- methyl-4-(8-methyl-3,8- diazabicyclo- [3.2.1]- octan-3- yl)phenyl)- pyrimidin-2-amine 0 1 H —CH₃ —

A 168 4-(4-(t- butylcarbonyl- amino)phenyl)- N-(3-methyl-4-(8-methyl-3,8- diazabicyclo- [3.2.1]- octan-3- yl)phenyl)- pyrimidin-2-amine 0 1 H —CH₃ —

A 169 4-(1H-pyrrol- 3-yl)-N-(3- methyl-4- ((1S,4S)- 5-methyl-2,5-diazabicyclo- [2.2.1]- heptan-2- yl)phenyl)- pyrimidin- 2-amine 0 1 H—CH₃ —

B 170 4-(1H-pyrrol- 3-yl)-N-(4- ((1S,4S)-5- methyl-2,5- diazabicyclo-[2.2.1]- heptan-2- yl)phenyl)- pyrimidin- 2-amine 0 0 H — —

B 171 4-(1H-pyrrol- 3-yl)-N-(3- trifluoro- methyl-4- ((1S,4S)-5-methyl-2,5- diazabicyclo- [2.2.1]- heptan-2- yl)phenyl)- pyrimidin-2-amine 0 1 H —CF₃ —

A 172 4-(2,2- dimethyl-3- oxo-3,4- dihydro- 2H-pyrido- [3,2-b][1,4]-oxazin-7-yl)- N-(3-tri- fluoromethyl- 4-((1S,4S)- 2,5- diazabicyclo-[2.2.1]- heptan-2- yl)phenyl)- pyrimidin- 2-amine 0 1 H —CF₃ —

A 173 4-(6-ethoxypyridin- 3-yl)-N-(3- methyl-4- ((1S,4S)-5- methyl-2,5-diazabicyclo- [2.2.1]- heptan-2- yl)phenyl)- pyrimidin- 2-amine 0 1 H—CH₃ —

A 174 4-(6-ethoxy- pyridin-3-yl)- N-(3-fluoro- 4-((1S,4S)- 5-methyl-2,5-diazabicyclo- [2.2.1]- heptan-2- yl)phenyl)- pyrimidin- 2-amine 0 1 H —F—

B 175 4-(2- (dimethyl amino)- thiazol-4-yl)- N-(3-methyl- 4-((1S,4S)-5-methyl-2,5- diazabicyclo- [2.2.1]- heptan-2- yl)phenyl)- pyrimidin-2-amine 0 1 H —CH₃ —

B 176 4-(2- (dimethyl- amino)- thiazol-4-yl)- N-(3-fluoro- 4-((1S,4S)-5-methyl-2,5- diazabicyclo- [2.2.1]- heptan-2- yl)phenyl)- pyrimidin-2-amine 0 1 H —F —

B 178 4-(5- (morpholin- 4-yl)pyrazin- 2-yl)-N- (3-methyl-4- ((1S,4S)-5-methyl-2,5- diazabicyclo- [2.2.1]- heptan-2- yl)phenyl)- pyrimidin-2-amine 0 1 H —CH₃ —

B 179 4-(5- (morpholin-4- yl)pyrazin-2- yl)-N-(3- fluoro-4- ((1S,4S)-5-methyl-2,5- diazabicyclo- [2.2.1]- heptan-2- yl)phenyl)- pyrimidin-2-amine 0 1 H —F —

B 181 4-(4-(1- ethoxyethyl)- phenyl)-N-(3- methyl-4- ((1S,4S)-5-methyl-2,5- diazabicyclo- [2.2.1]- heptan-2- yl)phenyl)- pyrimidin-2-amine 0 1 H —CH₃ —

B 182 4-(4-(1- ethoxyethyl)- phenyl)-N- (3-fluoro- 4-((1S,4S)-5-methyl-2,5- diazabicyclo- [2.2.1]- heptan-2- yl)phenyl)- pyrimidin-2-amine 0 1 H —F —

B 183 4-(6- (dimethyl- amino)- pyridin-3- yl)-N- (4-((1S,4S)-5-methyl-2,5- diazabicyclo- [2.2.1]- heptan-2- yl)phenyl)- pyrimidin-2-amine 0 0 H — —

A 184 4-(6- (morpholin-4- yl)pyridin-3- yl)-N- (4-((1S,4S)-5-methyl-2,5- diazabicyclo- [2.2.1]- heptan-2- yl)phenyl)- pyrimidin-2-amine 0 0 H — —

A 185 4-(4-methyl- 3,4-dihydro- 2H-pyrido- [3,2-b][1,4]- oxazin-7-yl)-N-(4-((1S,4S)- 5-methyl-2,5- diazabicyclo- [2.2.1]heptan-2- yl)phenyl)-pyrimidin- 2-amine 0 0 H — —

A 186 4-(6-(3- ethoxypropyl)- aminopyridin- 3-yl)-N-(3- methyl-4-((1S,4S)-5- methyl-2,5- diazabicyclo- [2.2.1]heptan- 2-yl)phenyl)-pyrimidin- 2-amine 0 1 H —CH₃ —

A 187 4-(6-(cis- 2,6-dimethyl- morpholin-4- yl)pyridin-3- yl)-N-(3-methyl-4- ((1S,4S)-5- methyl-2,5- diazabicyclo- [2.2.1]- heptan-2-yl)phenyl)- pyrimidin- 2-amine 0 1 H —CH₃ —

A 188 4-(6-(propyl- amino)- pyridin-3- yl)-N-(3- methyl-4- ((1S,4S)-5-methyl-2,5- diazabicyclo- [2.2.1]- heptan-2- yl)phenyl)- pyrimidin-2-amine 0 1 H —CH₃ —

A 189 4-(6-(2- (dimethyl- amino)- methyl- morpholin-4- yl)pyridin-3-yl)-N-(3- methyl-4- ((1S,4S)-5- methyl-2,5- diazabicyclo- [2.2.1]-heptan-2- yl)phenyl)- pyrimidin- 2-amine 0 1 H —CH₃ —

A 190 4-(6- (piperidin-1- yl)pyridin-3- yl)-N-(3- methyl-4- ((1S,4S)-5-methyl-2,5- diazabicyclo- [2.2.1]- heptan-2- yl)phenyl)- pyrimidin-2-amine 0 1 H —CH₃ —

A 191 4-(6-(3- (amino carbonyl)- piperidin-1- yl)pyridin-3- yl)-N-(3-methyl-4- ((1S,4S)-5- methyl-2,5- diazabicyclo- [2.2.1]- heptan-2-yl)phenyl)- pyrimidin- 2-amine 0 1 H —CH₃ —

B 192 4-(6- (morpholin-4- yl)pyridin-3- yl)-N-(3- methyl-4- ((1S,4S)-5-methyl sulfonyl-2,5- diazabicyclo- [2.2.1]- heptan-2- yl)phenyl)-pyrimidin- 2-amine 0 1 H —CH₃ —

A 193 4-(4-methyl- 3,4-dihydro- 2H-pyrido- [3,2-b][1,4]- oxazin-7-yl)-N-(3-methyl- 4-((1S,4S)- 5-methyl- sulfonyl- 2,5-diaza- bicyclo-[2.2.1]heptan-2- yl)phenyl)- pyrimidin- 2-amine 0 1 H —CH₃ —

A 194 4-(6- (morpholin-4- yl)pyridin-3- yl)-N-(3- methyl-4- ((1S,4S)-5-oxa-2- azabicyclo- [2.2.1]- heptan-2- yl)phenyl)- pyrimidin- 2-amine 0 1H —CH₃ —

A 195 4-(4-methyl- 3,4-dihydro- 2H-pyrido[3,2- b][1,4]oxazin-7-yl)-N-(3- methyl-4- ((1S,4S)-5- oxa-2- azabicyclo- [2.2.1]- heptan-2-yl)phenyl)- pyrimidin- 2-amine 0 1 H —CH₃ —

A 196 4-(6- (morpholin-4- yl)pyridin-3- yl)-N-(3- methyl-4- ((1S,4S)-5-ethylcarbonyl- 2,5- diazabicyclo- [2.2.1]- heptan-2- yl)phenyl)-pyrimidin- 2-amine 0 1 H —CH₃ —

A 197 4-(6-(2- (morpholin-4- yl)ethyl)- aminopyridin- 3-yl)-N-(3-methyl-4- ((1S,4S)-5- ethylcarbonyl- 2,5- diazabicyclo- [2.2.1]-heptan-2- yl)phenyl)- pyrimidin- 2-amine 0 1 H —CH₃ —

B 198 4-(6-(3- dimethyl- amino)- propylamino- pyridin- 3-yl)-N-(3-methyl-4- ((1S,4S)-5- methyl-2,5- diazabicyclo- [2.2.1]- heptan-2-yl)phenyl)- pyrimidin- 2-amine 0 1 H —CH₃ —

B 199 4-(6- (morpholin-4- yl)pyridin-3- yl)-N-(3- methyl-4- ((1S,4S)-5-amidino-2,5- diazabicyclo- [2.2.1]- heptan-2- yl)phenyl)- pyrimidin-2-amine. TFA salt 0 1 H —CH₃ —

B 200 4-(6-(3- ethoxypropyl)- aminopyridin- 3-yl)-N-(3- methyl-4-((1S,4S)-5- oxa-2- azabicyclo- [2.2.1]- heptan-2- yl)phenyl)- pyrimidin-2-amine 0 1 H —CH₃ —

A 201 4-(6-cis-2,6- dimethyl- morpholin-4- yl)pyridin-3- yl)-N-(3-methyl-4- ((1S,4S)-5- oxa-2- azabicyclo- [2.2.1]- heptan-2- yl)phenyl)-pyrimidin- 2-amine 0 1 H —CH₃ —

A 202 4-(6- (propylamino)- pyridin-3-yl)- N-(3-methyl- 4-((1S,4S)-5-oxa-2- azabicyclo- [2.2.1]- heptan-2- yl)phenyl)- pyrimidin- 2-amine 01 H —CH₃ —

A 203 4-(6-(3- dimethyl- amino)- propylamino- pyridin- 3-yl)-N-(3-methyl- 4-((1S,4S)- 5-oxa-2-azabicyclo- [2.2.1]- heptan-2-yl)phenyl)- pyrimidin- 2-amine 0 1 H —CH₃ —

A 204 4-(6-(1,4- oxazepan- 4-yl)pyridin- 3-yl)-N-(3- methyl-4-((1S,4S)-5- oxa-2- azabicyclo- [2.2.1]- heptan-2- yl)phenyl)- pyrimidin-2-amine 0 1 H —CH₃ —

A 205 4-(6- (morpholin-4- yl)pyridin-3- yl)-N-(3- methyl-4- ((1S,4S)-5-isobutyl-2,5- diazabicyclo- [2.2.1]- heptan-2- yl)phenyl)- pyrimidin-2-amine 0 1 H —CH₃ —

A 206 4-(6-(1,4-oxazepan- 4-yl)pyridin- 3-yl)-N-(3- methyl-4-((1S,4S)-5- methyl-2,5- diazabicyclo- [2.2.1]heptan- 2-yl)phenyl)-pyrimidin- 2-amine 0 1 H —CH₃ —

A 207 4-(2,2- dimethyl-3- oxo-3,4- dihydro-2H- pyrido[3,2-b][1,4]oxazin- 7-yl)-N- (3-methyl-4-(1,5,7- trimethyl-3,7- diazabicyclo-[3.3.1]- nonan-3- yl)phenyl)- pyrimidin- 2-amine 0 1 H —CH₃ —

A 208 4-(2,2- dimethyl-3- oxo-3,4- dihydro-2H- pyrido[3,2-b][1,4]oxazin- 7-yl)-N- (3-fluoro- 4-(1,5,7- trimethyl-3,7-diazabicyclo- [3.3.1]- nonan-3- yl)phenyl)- pyrimidin- 2-amine 0 1 H —F—

B 209 4-(3-oxo- 3,4-dihydro- 2H-pyrido [3,2-b][1,4]- oxazin-7- yl)-N-(3-methyl-4- ((1S,4S)-5- methyl-2,5- diazabicyclo- [2.2.1]- heptan-2-yl)phenyl)- pyrimidin- 2-amine 0 1 H —CH₃ —

A 210 4-(3-oxo-3,4- dihydro- 2H-pyrido [3,2-b][1,4]- oxazin-7- yl)-N-(3-methyl-4- ((1S,4S)-5- oxa-2- azabicyclo- [2.2.1]- heptan-2- yl)phenyl)-pyrimidin- 2-amine 0 1 H —CH₃ —

A 211 4-(6-(3- ethoxypropyl)- aminopyridin- 3-yl)-N-(3- methyl-4-(1,5,7- trimethyl-3,7- diazabicyclo- [3.3.1]nonan- 3-yl)phenyl)-pyrimidin- 2-amine 0 1 H —CH₃ —

A 212 4-(6-((2S,6R)- 2,6-dimethyl- morpholin- 4-yl)pyridin- 3-yl)-N-(3-methyl-4- (1,5,7- trimethyl-3,7- diazabicyclo- [3.3.1]- nonan-3-yl)phenyl)- pyrimidin- 2-amine 0 1 H —CH₃ —

A 213 4-(6-(propyl- amino)- pyridin-3- yl)-N-(3- methyl-4- (1,5,7-trimethyl-3,7- diazabicyclo- [3.3.1]- nonan-3- yl)phenyl)- pyrimidin-2-amine 0 1 H —CH₃ —

A 214 4-(6-(3- dimethyl- amino)- propylamino- pyridin- 3-yl)-N-(3-methyl- 4-(1,5,7- trimethyl-3,7- diazabicyclo- [3.3.1]nonan-3-yl)phenyl)- pyrimidin- 2-amine 0 1 H —CH₃ —

B 215 4-(6-((1S,4S)- 2-oxa-5- azabicyclo- [2.2.1]- heptan-5- yl)pyridin-3-yl)-N-(3- methyl- 4-((1S,4S)-5- methyl-2,5- diazabicyclo- [2.2.1]-heptan-2- yl)phenyl)- pyrimidin- 2-amine 0 1 H —CH₃ —

A 216 4-(6-((1S,4S)- 5-oxa-2- azabicyclo- [2.2.1]- heptan-2- yl)pyridin-3-yl)-N-(3- methyl-4- ((1S,4S)-5- oxa-2-azabicyclo- [2.2.1]- heptan-2-yl)phenyl)- pyrimidin- 2-amine 0 1 H —CH₃ —

A 217 4-(6-(3- methyl- butyl)- aminopyridin- 3-yl)-N-(3- methyl-4-((1S,4S)- 5-methyl-2,5- diazabicyclo- [2.2.1]- heptan-2- yl)phenyl)-pyrimidin- 2-amine 0 1 H —CH₃ —

A 218 4-(6-(3,3- dimethyl- butyl)- aminopyridin- 3-yl)-N- (3-methyl-4-((1S,4S)-5- methyl-2,5- diazabicyclo- [2.2.1]- heptan-2- yl)phenyl)-pyrimidin- 2-amine 0 1 H —CH₃ —

A 219 4-(6-(2- methoxy- ethyl)- (methyl)- aminopyridin- 3-yl)-N-(3-methyl-4- ((1S,4S)-5- methyl-2,5- diazabicyclo- [2.2.1]- heptan-2-yl)phenyl)- pyrimidin- 2-amine 0 1 H —CH₃ —

A 220 4-(6-(2- methoxy- ethyl)- (methyl)- amino- pyridin- 3-yl)-N-(3-methyl- 4-((1S,4S)- 5-oxa-2-azabicyclo- [2.2.1]- heptan-2-yl)phenyl)- pyrimidin- 2-amine 0 1 H —CH₃ —

A 221 4-(6-(2- methoxy- ethyl)- (methyl)- amino- pyridin- 3-yl)-N-(3-methyl-4- (1,5,7- trimethyl-3,7- diazabicyclo- [3.3.1]- nonan-3-yl)phenyl)- pyrimidin- 2-amine 0 1 H —CH₃ —

A 222 4-(6- (morpholin-4- yl)pyridin-3- yl)-N-(3- methyl-4- ((1S,4R)-2-azabicyclo- [2.2.1]- heptan-2- yl)phenyl)- pyrimidin- 2-amine 0 1 H —CH₃—

A 223 4-(2,2- dimethyl-3- oxo-3,4- dihydro- 2H-pyrido- [3,2-b][1,4]-oxazin-7-yl)- N-(3-methyl- 4-((1S,4R)-2- azabicyclo- [2.2.1]- heptan-2-yl)phenyl)- pyrimidin- 2-amine 0 1 H —CH₃ —

A 224 4-(2,2- dimethyl-3- oxo-3,4- dihydro- 2H-pyrido- [3,2-b][1,4]-oxazin-7-yl)- N-(3-methyl- 4-(2-methyl- sulfonyl-2- azabicyclo- [2.2.1]-heptan-5- yl)phenyl)- pyrimidin- 2-amine and 4-(2,2- dimethyl-3-oxo-3,4- dihydro-2H- pyrido[3,2- b][1,4]oxazin- 7-yl)-N-(3- methyl-4-(2-methyl- sulfonyl-2- azabicyclo- [2.2.1]- heptan-6- yl)phenyl)-pyrimidin- 2-amine (68:31) 0 1 H —CH₃ —

 

A 225 4-(6- (morpholin- 4-yl)pyridin- 3-yl)-N- (3-methyl- 4-(2-methyl-sulfonyl-2- azabicyclo- [2.2.1]-heptan- 5-yl)phenyl)- pyrimidin- 2-amineand 4-(6-( morpholin-4- yl)pyridin- 3-yl)-N-(3- methyl-4-(2- methyl-sulfonyl-2- azabicyclo- [2.2.1]- heptan-6- yl)phenyl)- pyrimidin-2-amine (85:15) 0 1 H —CH₃ —

B 226 4-(2,2- dimethyl-3- oxo-3,4- dihydro- 2H-pyrido [3,2-b][1,4]-oxazin- 7-yl)-N- (4-(2-methyl- sulfonyl-2- azabicyclo- [2.2.1]-heptan-5- yl)phenyl)- pyrimidin- 2-amine 0 0 H — —

B 227 4-(6- (morpholin-4- yl)pyridin-3- yl)-N-(4-(2- methyl- sulfonyl-2-azabicyclo- [2.2.1]- heptan-5- yl)phenyl)- pyrimidin- 2-amine 0 0 H — —

A 228 4-(2,2- dimethyl-3- oxo-3,4- dihydro- 2H-pyrido- [3,2-b][1,4]-oxazin-7-yl)- N-(4-(2- methyl- sulfonyl-2- azabicyclo- [2.2.1]-heptan-6- yl)phenyl)- pyrimidin- 2-amine 0 0 H — —

A 229 4-(6- (morpholin- 4-yl)pyridin- 3-yl)-N- (4-(2-methyl- sulfonyl-2-azabicyclo- [2.2.1]- heptan-6- yl)phenyl)- pyrimidin- 2-amine 0 0 H — —

B 230 4-(6-(thia- morpholin- 4-yl)pyridin- 3-yl)-N-(3- methyl-4-((1S,4S)-5- methyl-2,5- diazabicyclo- [2.2.1]heptan- 2-yl)phenyl)-pyrimidin- 2-amine 0 1 H —CH₃ —

A 231 4-(6- (morpholin-4- yl)pyridin-3- yl)-N-(3- methyl-4- ((1S,4S)-5-methyl-2,5- diazabicyclo- [2.2.1]- heptan-2- yl)phenyl)- pyrimidin-2-amine 0 1 H —CH₃ —

A 232 4-(1-(pyridin- 4-yl)-1H-indol- 5-yl)-N- (3-methyl-4- ((1S,4S)-5-methyl-2,5- diazabicyclo- [2.2.1]- heptan-2- yl)phenyl)- pyrimidin-2-amine 0 1 H —CH₃ —

A 233 4-(1-(pyridin- 4-yl)-1H- indol-5-yl)- N-(3-fluoro- 4-((1S,4S)-5-methyl-2,5- diazabicyclo- [2.2.1]- heptan-2- yl)phenyl)- pyrimidin-2-amine 0 1 H —F —

A 234 4-(1-(pyridin- 4-yl)-1H-indol- 5-yl)-N- (3-methyl-4- ((1S,4S)-5-ethyl-2,5- diazabicyclo- [2.2.1]- heptan-2- yl)phenyl)- pyrimidin-2-amine 0 1 H —CH₃ —

A 235 4-(1-(pyridin- 4-yl)-1H-indol- 5-yl)-N- (3-methyl-4- ((1S,4S)-5-isobutyl-2,5- diazabicyclo- [2.2.1]- heptan-2- yl)phenyl)- pyrimidin-2-amine 0 1 H —CH₃ —

A 237 4-(7-oxo- 5,6,7,8- tetrahydro- 1,8- naphthyridin- 3-yl)-N-(3-methyl-4- ((1S,4S)-5- methyl- sulfonyl-2,5- diazabicyclo- [2.2.1]-heptan-2- yl)phenyl)- pyrimidin- 2-amine 0 1 H —CH₃ —

A 238 4-(6- (propylamino)- pyridin-3-yl)- N-(3-methyl- 4-((1S,4S)-5-methyl- sulfonyl-2,5- diazabicyclo- [2.2.1]heptan- 2-yl)phenyl)-pyrimidin- 2-amine 0 1 H —CH₃ —

A 239 4-(3-oxo-3,4- dihydro-2H- benzo[b][1,4]- thiazin-7- yl)-N-(4-((1S,4S)-5- methyl-2,5- diazabicyclo- [2.2.1]- heptan-2- yl)phenyl)-pyrimidin- 2-amine 0 0 H — —

A 240 4-(2,2- dimethyl- 3-oxo-3,4-dihydro-2H- benzo[b][1,4]-oxazin-7-yl)- N-(3-methyl- 4-((1S,4S)- 5-methyl-2,5- diazabicyclo-[2.2.1]- heptan-2- yl)phenyl)- pyrimidin- 2-amine 0 1 H —CH₃ —

A 241 4-(2,2- dimethyl-3- oxo-3,4- dihydro-2H- benzo[b][1,4]-oxazin-7-yl)- N-(3-methyl- 4-((1S,4S)- 5-methyl- sulfonyl-2,5-diazabicyclo- [2.2.1]- heptan-2- yl)phenyl)- pyrimidin- 2-amine 0 1 H—CH₃ —

A 242 4-(2-oxo- 2,3,4,5- tetrahydro- 1H-benzo[b]- azepin-7-yl)-N-(3-methyl- 4-((1S,4S)-5- methyl-2,5- diazabicyclo- [2.2.1]- heptan-2-yl)phenyl)- pyrimidin- 2-amine 0 1 H —CH₃ —

A 243 4-(2-oxo- 2,3,4,5- tetrahydro- 1H-benzo[b]- azepin-7-yl)-N-(3-methyl- 4-((1S,4S)-5- methylsulfonyl-2,5- diazabicyclo- [2.2.1]-heptan-2- yl)phenyl)- pyrimidin- 2-amine 0 1 H —CH₃ —

A 244 4-(2,2- dimethyl-3- oxo-3,4- dihydro-2H- benzo[b][1,4]-oxazin-7-yl)- N-(3-methyl- 4-((6R,9S)- 6,9-methano- octahydro-1H-pyrido[1,2- a]pyrazin-2- yl)phenyl)- pyrimidin-2- amine 0 1 H —CH₃ —

A 245 4-(6- (morpholin-4- yl)pyridin-3- yl)-N-(3- methyl-4-((6R,9S)-6,9- methano- octahydro- 1H-pyrido[1,2- a]pyrazin-2-yl)phenyl)- pyrimidin-2- amine 0 1 H —CH₃ —

A 246 4-(2,2- dimethyl-3- oxo-3,4- dihydro-2H- pyrido[3,2- b][1,4]-oxazin-7-yl)- N-(3-methyl- 4-((1S,4S)- 5-(1-methyl- ethyl)-2,5-diazabicyclo- [2.2.1]- heptan-2- yl)phenyl)- pyrimidin- 2-amine 0 1 H—CH₃ —

A 247 4-(2,2- dimethyl-3- oxo-3,4- dihydro-2H- pyrido[3,2-b][1,4]oxazin- 7-yl)-N- (3-methyl-4- ((1S,4S)-5- cyclopropyl- 2,5-diazabicyclo- [2.2.1]heptan- 2-yl)phenyl)- pyrimidin- 2-amine 0 1 H —CH₃—

A 248 4-(2,2- dimethyl-3- oxo-3,4- dihydro-2H- pyrido[3,2-b][1,4]oxazin- 7-yl)-N-(3- chloro-4- ((1S,4S)-5- methyl-2,5-diazabicyclo- [2.2.1]- heptan-2- yl)phenyl)- pyrimidin- 2-amine 0 1 H—Cl —

A 249 4-(2,2- dimethyl-3- oxo-3,4- dihydro-2H- pyrido[3,2-b][1,4]oxazin- 7-yl)-N-(3- chloro-4- ((1S,4S)-5- (methyl- sulfonyl)-2,5-diazabicyclo- [2.2.1]- heptan-2- yl)phenyl)- pyrimidin- 2-amine 0 1 H—Cl —

A 250 4-(2,2- dimethyl-3- oxo-3,4- dihydro-2H- pyrido[3,2-b][1,4]oxazin- 7-yl)-N-(3- methyl-4- ((1S,4S)-5- cyclopentyl- 2,5-diazabicyclo- [2.2.1]heptan- 2-yl)phenyl)- pyrimidin- 2-amine 0 1 H —CH₃—

A 251 4-(2,2- dimethyl- 3-oxo-3,4-dihydro-2H- pyrido[3,2- b][1,4]oxazin-7-yl)-N- (3-methyl-4- ((1S,4S)-5- acetyl-2,5- diazabicyclo- [2.2.1]-heptan-2- yl)phenyl)- pyrimidin- 2-amine 0 1 H —CH₃ —

A 252 4-(2,2- dimethyl-3- oxo-3,4- dihydro-2H- pyrido[3,2-b][1,4]oxazin- 7-yl)-N- (3-methyl- 4-(1,4- diazabicyclo- [3.2.1]-octan-4- yl)phenyl)- pyrimidin- 2-amine 0 1 H —CH₃ —

A 253 4-(5-(1- methyl- ethoxy)- carbonyl- propyl-6- amino- pyridin-3-yl)-N-(3- methyl-4- ((1S,4S)-5- methyl-2,5- diazabicyclo- [2.2.1]-heptan-2- yl)phenyl)- pyrimidin- 2-amine; 0 1 H —CH₃ —

A 254 4-(6- (morpholin-4- yl)pyridin-3- yl)-N-(3- methyl-4- ((1S,4S)-5-cyclopropyl- 2,5- diazabicyclo- [2.2.1]heptan- 2-yl)phenyl)- pyrimidin-2-amine 0 1 H —CH₃ —

A 255 4-(6- (morpholin-4- yl)pyridin-3- yl)-N-(3- chloro-4- ((1S,4S)-5-methyl-2,5- diazabicyclo- [2.2.1]- heptan-2- yl)phenyl)- pyrimidin-2-amine 0 1 H —Cl —

A 256 4-(2-(tri- fluoromethyl)- pyridin-4-yl)- N-(3-methyl-4-((1S,4S)-5- methyl-2,5- diazabicyclo- [2.2.1]- heptan-2- yl)phenyl)-pyrimidin- 2-amine 0 1 H —CH₃ —

A 257 4-(6- (morpholin-4- yl)pyridin-3- yl)-N-(3- chloro-4- ((1S,4S)-5-(methyl- sulfonyl)-2,5- diazabicyclo- [2.2.1]- heptan-2- yl)phenyl)-pyrimidin- 2-amine 0 1 H —Cl —

A 258 4-(6- (tetrahydro- pyran-4- yloxy)pyridin- 3-yl)-N-(3- chloro-4-((1S,4S)-5- (methyl- sulfonyl)-2,5- diazabicyclo- [2.2.1]- heptan-2-yl)phenyl)- pyrimidin- 2-amine 0 1 H —Cl —

B 259 4-(6- (morpholin- 4-yl)pyridin- 3-yl)-N-(3- chloro-4- ((1S,4S)-5-acetyl-2,5- diazabicyclo- [2.2.1]- heptan-2- yl)phenyl)- pyrimidin-2-amine 0 1 H —Cl —

A 260 4-(6- (tetrahydro- pyran-4- yloxy)- pyridin-3- yl)-N-(3- chloro-4-((1S,4S)-5- acetyl-2,5- diazabicyclo- [2.2.1]- heptan-2- yl)phenyl)-pyrimidin- 2-amine 0 1 H —Cl —

B 261 4-(6-(tetra- hydropyran-4- yloxy)pyridin- 3-yl)-N-(3- methyl-4-((1S,4S)- 5-methyl-2,5- diazabicyclo- [2.2.1]- heptan-2- yl)phenyl)-pyrimidin- 2-amine 0 1 H —CH₃ —

A 262 4-(6- (tetrahydro- pyran-4- yloxy)pyridin- 3-yl)-N-(3- methyl-4-((1S,4S)-5- cyclopentyl- 2,5- diazabicyclo- [2.2.1]- heptan-2-yl)phenyl)- pyrimidin- 2-amine 0 1 H —CH₃ —

A 263 4-(6- (morpholin-4- yl)pyridin-3- yl)-N-(3- chloro-4-((1S,4S)-5-(1- methylethyl)- 2,5- diazabicyclo- [2.2.1]- heptan-2-yl)phenyl)- pyrimidin- 2-amine 0 1 H —CH₃ —

A 264 4-(6-((1S,4S)- 2-oxa-5- azabicyclo- [2.2.1]- heptan-5- yl)pyridin-3-yl)-N-(3- methyl- 4-((1S,4S)- 5-(methyl- sulfonyl)-2,5- diazabicyclo-[2.2.1]- heptan-2- yl)phenyl)- pyrimidin- 2-amine 0 1 H —CH₃ —

A 265 4-(6-((1R,4R)- 2-oxa-5- azabicyclo- [2.2.1]- heptan-5- yl)pyridin-3-yl)-N-(3- methyl-4- ((1S,4S)-5- methyl-2,5- diazabicyclo- [2.2.1]-heptan-2- yl)phenyl)- pyrimidin- 2-amine 0 1 H —CH₃ —

A 267 4-(6,7,8,9- tetrahydro- 5H-pyrido- [2,3-b]indol- 3-yl)-N-(3-methyl-4- ((1S,4S)- 5-methyl-2,5- diazabicyclo- [2.2.1]- heptan-2-yl)phenyl)- pyrimidin- 2-amine 0 1 H —CH₃ —

B 268 4-(6,7,8,9- tetrahydro- 5H-pyrido- [2,3-b]indol- 3-yl)-N-(3-methyl- 4-((1S,4S)- 5-(methyl- sulfonyl)-2,5- diazabicyclo- [2.2.1]-heptan-2- yl)phenyl)- pyrimidin- 2-amine 0 1 H —CH₃ —

B 269 4-(4-(tri fluoromethyl)- phenyl)-N-(3- methyl-4- ((1S,4S)-5-methyl-2,5- diazabicyclo- [2.2.1]- heptan-2- yl)phenyl)- pyrimidin-2-amine 0 1 H —CH₃ —

A 270 4-(7,8,9,9a- tetrahydro- 5H-pyrido- [2,3-e]- pyrrolo[1,2-a][1,4]diazepin- 10(11H)- on-3-yl)-N- (3-methyl-4- ((1S,4S)-5-methyl-2,5- diazabicyclo- [2.2.1]- heptan-2- yl)phenyl)- pyrimidin-2-amine 0 1 H —CH₃ —

A 271 4-(2,2- dimethyl-3- oxo-3,4- dihydro-2H- benzo[b][1,4]-oxazin-7-yl)- N-(3-cyano- 4-((1S,4S)- 5-methyl-2,5- diazabicyclo-[2.2.1]- heptan-2- yl)phenyl)- pyrimidin- 2-amine 0 1 H —CN —

A 272 4-(2-oxo- 2,3,4,5- tetrahydro- 1H-benzo[b]- azepin-7-yl)-N-(3-cyano- 4-((1S,4S)-5- methyl-2,5- diazabicyclo- [2.2.1]- heptan-2-yl)phenyl)- pyrimidin- 2-amine 0 1 H —CN —

A 273 4-(3-oxo-3,4- dihydro-2H- benzo[b][1,4]- thiazin- 7-yl)-N-(3-cyano-4- ((1S,4S)- 5-methyl-2,5- diazabicyclo- [2.2.1]- heptan-2-yl)phenyl)- pyrimidin- 2-amine 0 1 H —CN —

A 274 4-(3-oxo-3,4- dihydro-2H- benzo[b][1,4]- thiazin- 7-yl)-N-(3-methyl-4- ((1S,4S)- 5-methyl-2,5- diazabicyclo- [2.2.1]- heptan-2-yl)phenyl)- pyrimidin- 2-amine 0 1 H —CH₃ —

A 275 4-(6-(tetra- hydropyran- 4-yloxy)- pyridin-3- yl)-N-(3- methyl-4-(1,4- diazabicyclo- [3.2.1]octan-4- yl)phenyl)- pyrimidin- 2-amine 0 1 H—CH₃ —

A 276 4-(6- (morpholin- 4-yl)-pyridin- 3-yl)-N-(3- methyl- 4-((R)-1,4-diazabicyclo- [3.2.1]- octan-4- yl)phenyl)- pyrimidin- 2-amine 0 1 H—CH₃ —

A 277 4-(6- (morpholin-4- yl)pyridin-3- yl)-N-(3- methyl- 4-((S)-1,4-diazabicyclo- [3.2.1]- octan-4- yl)phenyl)- pyrimidin- 2-amine 0 1 H—CH₃ —

A 278 4-(2-oxo- 2,3,4,5- tetrahydro- 1H-benzo[b]- azepin-7-yl)-N-(3-methyl-4- ((6R,9S)-6,9- methano- octahydro-1H- pyrido[1,2-a]-pyrazin-2- yl)phenyl)- pyrimidin- 2-amine 0 1 H —CH₃ —

A 279 4-(3-oxo-3,4- dihydro-2H- benzo[b][1,4]- thiazin-7-yl)-N-(3-methyl- 4-((6R,9S)- 6,9-methano- octahydro- 1H-pyrido[1,2-a]pyrazin-2- yl)phenyl)- pyrimidin-2- amine 0 1 H —CH₃ —

A 280 4-(6-((1S,4S)- 2-oxa-5- azabicyclo- [2.2.1]- heptan-5- yl)pyridin-3-yl)-N- (3-methyl- 4-(1,4- diazabicyclo- [3.2.2]- nonan-4- yl)phenyl)-pyrimidin- 2-amine 0 1 H —CH₃ —

A 281 4-(6- (morpholin-4- yl)pyridin-3- yl)-N-(3- cyano-4-(3,9-diazabicyclo- [3.3.2]- decan-10-on- 3-yl)phenyl)- pyrimidin- 2-amine 0 1H —CN —

— 282 4-(2,2- dimethyl-3- oxo-3,4- dihydro-2H- pyrido[3,2-b][1,4]oxazin- 7-yl)-N-(3- cyano-4-(3,9- diazabicyclo- [3.3.2]-decan-10-on- 3-yl)phenyl)- pyrimidin- 2-amine 0 1 H —CN —

— 283 4-(6-(tetra hydropyran-4- yloxy)pyridin- 3-yl)-N-(3- methyl-4-(3-(dimethyl- amino)-8- azabicyclo- [3.2.1]- octan-8- yl)phenyl)-pyrimidin- 2-amine 0 1 H —CH₃ —

A 284 4-(6- (morpholin- 4-yl)pyridin- 3-yl)-N- (3-methyl-4-(3-(morpholin- 4-yl)-8- azabicyclo- [3.2.1]- octan-8- yl)phenyl)-pyrimidin- 2-amine 0 1 H —CH₃ —

A 285 4-(6-(tetra- hydropyran- 4-yloxy)- pyridin-3- yl)-N-(3- methyl-4-(3-(morpholin- 4-yl)-8- azabicyclo- [3.2.1]- octan-8- yl)phenyl)-pyrimidin- 2-amine 0 1 H —CH₃ —

A 286 4-(6- (morpholin-4- yl)pyridin-3- yl)-N-(3- methyl-4-(3-(dimethyl- amino)-8- azabicyclo- [3.2.1]- octan-8- yl)phenyl)- primidin-2-amine 0 1 H —CH₃ —

A

TABLE 3 (Ia-2)

Cpd # Compound Name n m R¹ R² R³ R⁴ R⁵ IC₅₀ 544-(6-(dimethylamino)pyridin-3-yl)-N- (6-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2- yl)pyridin-3-yl)pyrimidin-2-amine 0 0 H — —

B 55 4-(6-(methylcarbonylamino)pyridin-3-yl)-N-(4-((1S,4S)-5-methyl-2,5- diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)pyrimidin-2-amine 0 0 H — —

B 56 4-(4-(dimethylamino)phenyl)-N-(6- ((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2- yl)pyridin-3-yl)pyrimidin-2-amine 0 0 H — —

B 57 4-(6-(4-acetylpiperazin-1-yl)pyridin-3-yl)-N-(6-((1S,4S)-5-methyl-2,5- diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)pyrimidin-2-amine 0 0 H — —

B 58 4-(5-methyl-6-(morpholin-4- yl)pyridin-3-yl)-N-(6-((1S,4S)-5-methyl-2,5- diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)pyrimidin-2-amine 0 0 H — —

B 61 4-(6-(dimethylamino)pyridin-3-yl)-N-(5-methyl-6-((1S,4S)-5-methyl-2,5- diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)pyrimidin-2-amine 0 1 H —CH₃ —

A 62 4-(4-(dimethylamino)phenyl)-N-(5- methyl-6-((1S,4S)-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2- yl)pyridin-3-yl)pyrimidin-2-amine 0 1 H—CH₃ —

B 63 4-(6-(4-acetylpiperazin-1-yl)pyridin-3-yl)-N-(5-methyl-6-((1S,4S)-5-methyl- 2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)pyrimidin-2-amine 0 1 H —CH₃ —

B 64 4-(5-methyl-6-(morpholin-4- yl)pyridin-3-yl)-N-(5-methyl-6-((1S,4S)-5-methyl-2,5- diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)pyrimidin-2-amine 0 1 H —CH₃ —

A 65 4-(4-methyl-3,4-dihydro-2H- pyrido[3,2-b][1,4]oxazin-7-yl)-N-(5-methyl-6-((1S,4S)-5-methyl-2,5- diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)pyrimidin-2-amine 0 1 H —CH₃ —

A 66 4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(5-methyl-6-((1S,4S)-5-methyl-2,5- diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)pyrimidin-2-amine 0 1 H —CH₃ —

B 131 4-(4-(t-butylcarbonylamino)phenyl)-N-(5-methyl-6-((1S,4S)-5-methyl-2,5- diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)pyrimidin-2-amine 0 1 H —CH₃ —

A 138 4-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N- (5-methyl-6-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2- yl)pyridin-3-yl)pyrimidin-2-amine 0 1 H—CH₃ —

A 140 4-(4-(3-cyclopropylureido)phenyl)-N-(5-methyl-6-((1S,4S)-5-methyl-2,5- diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)pyrimidin-2-amine 0 1 H —CH₃ —

B 144 4-(6-(2-(morpholin-4- yl)acetamido)pyridin-3-yl)-N-(5-methyl-6-((1S,4S)-5-methyl-2,5- diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)pyrimidin-2-amine 0 1 H —CH₃ —

B 145 4-(6-aminopyridin-3-yl)-N-(5-methyl- 6-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2- yl)pyridin-3-yl)pyrimidin-2-amine 0 1 H—CH₃ —

A 146 4-(6-(acetamido)pyridin-3-yl)-N-(5-methyl-6-((1S,4S)-5-methyl-2,5- diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)pyrimidin-2-amine 0 1 H —CH₃ —

B 154 4-(6-(methylsulfonylamino)pyridin-3-yl)-N-(5-methyl-6-((1S,4S)-5-methyl- 2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)pyrimidin-2-amine 0 1 H —CH₃ —

D 177 4-(2-(dimethylamino)thiazol-4-yl)-N- (6-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2- yl)pyridin-3-yl)pyrimidin-2-amine 0 0 H — —

D 180 4-(5-(morpholin-4-yl)pyrazin-2-yl)-N- (6-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2- yl)pyridin-3-yl)pyrimidin-2-amine 0 0 H — —

B 236 4-(1-(pyridin-4-yl)-1H-indol-5-yl)-N-(5-methyl-6-((1S,4S)-5-methyl-2,5- diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)pyrimidin-2-amine 0 1 H —CH₃ —

A 266 4-(6-((1S,4S)-2-oxa-5- azabicyclo[2.2.1]heptan-5-yl)pyridin-3-yl)-N-(5-methyl-6-((1S,4S)-5- methyl-2,5- diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)pyrimidin-2-amine 0 1 H —CH₃ —

A IC₅₀ activity: A = <1 μM B = 1 to 10 μM C = >10 to 20 μM D = >20 μM

All of the U.S. patents, U.S. patent application publications, U.S.patent applications, foreign patents, foreign patent applications andnon-patent publications referred to in this specification and/or listedin the Application Data Sheet are incorporated herein by reference, intheir entireties.

Although the foregoing invention has been described in some detail tofacilitate understanding, it will be apparent that certain changes andmodifications may be practiced within the scope of the appended claims.Accordingly, the described embodiments are to be considered asillustrative and not restrictive, and the invention is not to be limitedto the details given herein, but may be modified within the scope andequivalents of the appended claims.

What is claimed is:
 1. A method of treating, but not preventing, adisease or condition associated with JAK2 activity in a mammal, whereinthe method comprises administering to the mammal a therapeuticallyeffective amount of4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,or a pharmaceutically acceptable salt thereof, and the disease orcondition is polycythemia vera disorder, essential thrombocythemiadisorder or primary myelofibrosis.
 2. A method of treating, but notpreventing, a disease or condition associated with JAK2 activity in amammal, wherein the method comprises administering to the mammal apharmaceutical composition comprising a pharmaceutically acceptableexcipient and a therapeutically effective amount of4-(6-(morpholin-4-yl)pyridin-3-yl)-N-(3-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine,or a pharmaceutically acceptable salt thereof, and the disease orcondition is polycythemia vera disorder, essential thrombocythemiadisorder or primary myelofibrosis.
 3. The method of claim 1 wherein thedisease or condition is polycythemia vera disorder.
 4. The method ofclaim 1 wherein the disease or condition is essential thrombocythemiadisorder.
 5. The method of claim 1 wherein the disease or condition isprimary myelofibrosis.
 6. The method of claim 2 wherein the disease orcondition is polycythemia vera disorder.
 7. The method of claim 2wherein the disease or condition is essential thrombocythemia disorder.8. The method of claim 2 wherein the disease or condition is primarymyelofibrosis.